Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors

ABSTRACT

The invention provides certain thiazole-substituted aminoheteroaryl compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein R 1 , R 3 , R 5 , R 6 , A, Cy and the subscripts r, s, and t are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the compounds for treating diseases or conditions mediated by Spleen Tyrosine Kinase (Syk).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT/US2014/070239, filed Dec. 15, 2014, which claims priorityfrom U.S. provisional application No. 61/918,980 filed Dec. 20, 2013.

FIELD OF THE INVENTION

The present invention relates to certain thiazole-substitutedaminoheteroaryl compounds of the Formula (I) (also referred to herein asthe “compounds of the Formula (I)” or “compounds of Formula (I)”) whichare inhibitors of Spleen Tyrosine Kinase (Syk) kinase activity, or areprodrugs thereof. The present invention also provides compositionscomprising such compounds, and methods of using such compounds fortreating conditions or disorders associated with inappropriate Sykactivity, in particular in the treatment and prevention of diseasestates mediated by Syk. Such disease states may include inflammatory,allergic and autoimmune diseases, for example, asthma, chronicobstructive pulmonary disease (COPD), adult respiratory distresssyndrome (ARDS), ulcerative colitis, Crohns disease, bronchitis,dermatitis, allergic rhinitis, psoriasis, scleroderma, urticaria,rheumatoid arthritis, idiopathic thrombocytopenic purpura (ITP),multiple sclerosis, cancer, HIV and lupus.

BACKGROUND OF THE INVENTION

Spleen Tyrosine Kinase (Syk) is a protein tyrosine kinase which has beendescribed as a key mediator of immunoreceptor signalling in a host ofinflammatory cells including mast cells, B-cells, macrophages andneutrophils. These immunoreceptors, including Fc receptors and theB-cell receptor, are important for both allergic diseases andantibody-mediated autoimmune diseases and thus pharmacologicallyinterfering with Syk could conceivably treat these disorders.

Allergic rhinitis and asthma are diseases associated withhypersensitivity reactions and inflammatory events involving a multitudeof cell types including mast cells, eosinophils, T cells and dendriticcells. Following exposure to allergen, high affinity immunoglobulinreceptors for IgE and IgG become cross-linked and activate downstreamprocesses in mast cells and other cell types leading to the release ofpro-inflammatory mediators and airway spasmogens. In the mast cell, forexample, IgE receptor cross-linking by allergen leads to release ofmediators including histamine from pre-formed granules, as well as thesynthesis and release of newly synthesized lipid mediators includingprostaglandins and leukotrienes.

Syk kinase is a non-receptor linked tyrosine kinase which is importantin transducing the downstream cellular signals associated withcross-linking Fc_(epsilon)RI and or Fc_(epsilon)RI receptors, and ispositioned early in the signalling cascade. In mast cells, for example,the early sequence of Fc_(epsilon)RI signalling following allergencross-linking of receptor-IgE complexes involves first Lyn (a Src familytyrosine kinase) and then Syk. Inhibitors of Syk activity wouldtherefore be expected to inhibit all downstream signalling cascadesthereby alleviating the immediate allergic response and adverse eventsinitiated by the release of pro-inflammatory mediators and spasmogens(Wong et al. 2004, Expert Opin. Investig. Drugs (2004) 13 (7) 743-762).

Recently, it has been shown that the Syk kinase inhibitor R112 (Rigel),dosed intranasally in a phase I/II study for the treatment of allergicrhinitis, gave a statistically significant decrease in PGD₂, a keyimmune mediator that is highly correlated with improvements in allergicrhinorrhea, as well as being safe across a range of indicators, thusproviding the first evidence for the clinical safety and efficacy of atopical Syk kinase inhibitor. (Meltzer, Eli O.; Berkowitz, Robert B.;Grossbard, Elliott B, Journal of Allergy and Clinical Immunology (2005),115(4), 791-796). In a more recent phase II clinical trial for allergicrhinitis (Clinical Trials.gov Identifier NCT0015089), R112 was shown ashaving a lack of efficacy versus placebo.

Rheumatoid Arthritis (RA) is an auto-immune disease affectingapproximately 1% of the population. It is characterised by inflammationof articular joints leading to debilitating destruction of bone andcartilage. Recent clinical studies with Rituximab, which causes areversible B cell depletion, (J. C. W. Edwards et al. 2004, New Eng. J.Med. 350: 2572-2581) have shown that targeting B cell function is anappropriate therapeutic strategy in auto-immune diseases such as RA.Clinical benefit correlates with a reduction in auto-reactive antibodies(or Rheumatoid Factor) and these studies suggest that B cell functionand indeed auto-antibody production are central to the ongoing pathologyin the disease.

Studies using cells from mice deficient in the Spleen Tyrosine Kinase(Syk) have demonstrated a non-redundant role of this kinase in B cellfunction. The deficiency in Syk is characterised by a block in B celldevelopment (M. Turner et al. 1995 Nature 379: 298-302 and Cheng et al.1995, Nature 378: 303-306). These studies, along with studies on matureB cells deficient in Syk (Kurasaki et al. 2000, Immunol. Rev.176:19-29), demonstrate that Syk is required for the differentiation andactivation of B cells. Hence, inhibition of Syk in RA patients is likelyto block B cell function, and thereby reduce Rheumatoid Factorproduction. In addition to the role of Syk in B cell function, and offurther relevance to the treatment of RA, is the requirement for Sykactivity in Fc receptor (FcR) signalling. FcR activation by immunecomplexes in RA has been suggested to contribute to the release ofmultiple pro-inflammatory mediators.

SUMMARY OF THE INVENTION

The present invention provides novel compounds that are potentinhibitors of Syk, or are prodrugs thereof, as well as pharmaceuticalcompositions containing them. As Syk inhibitors compounds of Formula (I)are useful in the treatment and prevention of diseases and disordersmediated by the Syk protein; such diseases and disorders include, butare not limited to, asthma, COPD, rheumatoid arthritis, cancer andidiopathic thrombocytopenic purpura.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names, and chemical structures may be used interchangeablyto describe the same structure. If a chemical compound is referred tousing both a chemical structure and a chemical name, and an ambiguityexists between the structure and the name, the structure predominates.These definitions apply regardless of whether a term is used by itselfor in combination with other terms, unless otherwise indicated. Hence,the definition of “alkyl” applies to “alkyl” as well as the “alkyl”portions of “hydroxyalkyl,” “fluoroalkyl,” “—O-alkyl,” etc.

As used herein, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

A “patient” is a human or non-human mammal. In one embodiment, a patientis a human. In another embodiment, a patient is a chimpanzee.

The term “therapeutically effective amount” as used herein, refers to anamount of the compound of Formula (I) and/or an additional therapeuticagent, or a composition thereof that is effective in producing thedesired therapeutic, ameliorative, inhibitory or preventative effectwhen administered to a patient suffering from a disease or conditionmediated by Syk. In the combination therapies of the present invention,a therapeutically effective amount can refer to each individual agent orto the combination as a whole, wherein the amounts of all agentsadministered are together effective, but wherein the component agent ofthe combination may not be present individually in an effective amount.

The term “preventing,” as used herein with respect to cancer or aninflammatory disease or disorder, refers to reducing the likelihood ofcancer pain or an inflammatory disease or disorder.

The term “alkyl,” as used herein, refers to an aliphatic hydrocarbongroup having one of its hydrogen atoms replaced with a bond having thespecified number of carbon atoms. In different embodiments, an alkylgroup contains from 1 to 6 carbon atoms (C₁-C₆ alkyl) or from 1 to 3carbon atoms (C₁-C₃ alkyl). Non-limiting examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyland neohexyl. In one embodiment, an alkyl group is linear. In anotherembodiment, an alkyl group is branched.

The term “alkenyl,” as used herein, refers to an aliphatic hydrocarbongroup containing at least one carbon-carbon double bond and having oneof its hydrogen atoms replaced with a bond. An alkenyl group may bestraight or branched and contain from about 2 to about 15 carbon atoms.In one embodiment, an alkenyl group contains from about 3 to 6 carbonatoms. Non-limiting examples of alkenyl groups include ethenyl,propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl anddecenyl. The term “C₂-C₆ alkenyl” refers to an alkenyl group having from2 to 6 carbon atoms. Unless otherwise indicated, an alkenyl group isunsubstituted.

The term “fluoroalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshas been replaced with a fluorine. In one embodiment, a fluoroalkylgroup has from 1 to 6 carbon atoms. In another embodiment, a fluoroalkylgroup has from 1 to 3 carbon atoms. In another embodiment, a fluoroalkylgroup is substituted with from 1 to 3 F atoms. Non-limiting examples offluoroalkyl groups include —CH₂F, —CHF₂, and —CF₃. The term “C₁-C₃fluoroalkyl” refers to a fluoroalkyl group having from 1 to 3 carbonatoms.

The term “alkoxy” as used herein, refers to an —O-alkyl group, whereinan alkyl group is as defined above. Non-limiting examples of alkoxygroups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy andt-butoxy. An alkoxy group is bonded via its oxygen atom to the rest ofthe molecule.

The term “aryl,” as used herein, refers to an aromatic monocyclic ormulticyclic ring system comprising from about 6 to about 14 carbonatoms. In one embodiment, an aryl group contains from about 6 to 10carbon atoms (C₆-C₁₀ aryl). In another embodiment an aryl group isphenyl. Non-limiting examples of aryl groups include phenyl andnaphthyl.

The term “carbocycle,” as used herein, refers to a fully saturated orpartially unsaturated, monocyclic or multicyclic ring system comprisingfrom about 3 to 12 carbon atoms. In one embodiment, the carbocyclicgroup contains from 4 to 12 carbon atoms. Non-limiting examples ofcarbocyclic groups include cycloalkyl groups, as defined herein. Inspecific embodiments, the carbocylic groups are selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.2.1]octyl,and spiro[3.5]nonyl.

The term “cycloalkyl,” as used herein, refers to a saturated ringcontaining the specified number of ring carbon atoms, and no heteroatom.In a like manner the term “C₃-C₆ cycloalkyl” refers to a saturated ringhaving from 3 to 6 ring carbon atoms. Non-limiting examples ofmonocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

The term “halo,” as used herein, means —F, —Cl, —Br or —I. In oneembodiment, a halo group is —F or —Cl. In another embodiment, a halogroup is —F.

The term “heteroaryl,” as used herein, refers to an aromatic monocyclicor multicyclic ring system comprising about 5 to about 14 ring atoms,wherein from 1 to 3 of the ring atoms is independently N, O, or S andthe remaining ring atoms are carbon atoms. In one embodiment, aheteroaryl group has 5 to 10 ring atoms. In another embodiment, aheteroaryl group is monocyclic ring system and has 5 or 6 ring atoms. Inanother embodiment, a heteroaryl group is a bicyclic ring system. Aheteroaryl group is joined via a ring carbon atom. The term “heteroaryl”also includes a heteroaryl as defined above fused to a heterocycle asdefined below. The term “heteroaryl” also encompasses a heteroarylgroup, as defined above, which is fused to a benzene, a cyclohexadieneor a cyclohexene ring. Non-limiting examples of heteroaryls includepyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (includingN-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl,oxadiazolyl, thiazolyl, pyrazolyl, furyl, pyrrolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, indolyl, quinoxalinyl,phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl,imidazo[2,1-b]thiazolyl, and the like. In one embodiment, a heteroarylgroup is a 5-membered heteroaryl. In another embodiment, a heteroarylgroup is a 6-membered heteroaryl.

The term “heterocyclyl” or “heterocycle”,” as used herein, refers to anon-aromatic saturated or partially saturated monocyclic or multicyclicring system containing 3 to 11 ring atoms, wherein from 1 to 4 of thering atoms are independently O, S, or N, and the remainder of the ringatoms are carbon atoms. In one embodiment, a heterocyclyl group ismonocyclic and has from 3 to 7 ring atoms. In another embodiment, aheterocyclyl group is monocyclic and has from about 4 to 7 ring atoms.In another embodiment, a heterocyclyl group is bicyclic and has from 7to 11 ring atoms. In still another embodiment, a heterocyclyl group ismonocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocyclylgroup is monocyclic. In another embodiment, a heterocyclyl group isbicyclic. A heterocyclyl group can be joined to the rest of the moleculevia a ring carbon or ring nitrogen atom. The nitrogen or sulfur atom ofthe heterocyclyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of monocyclicheterocyclyl rings include oxetanyl, piperidyl, pyrrolidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,dihydropyranyl, pyran, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, delta-lactam, delta-lactone, and the like.

The term “substituted” means that one or more hydrogens on the atoms ofthe designated are replaced with a selection from the indicated group,provided that the atoms' normal valencies under the existingcircumstances are not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

When any substituent or variable occurs more than one time in anyconstituent or the compound of Formula (I), its definition on eachoccurrence is independent of its definition at every other occurrence,unless otherwise indicated. For example, description of radicals whichinclude the expression “—N(C₁-C₃ alkyl)₂” means —N(CH₃)(CH₂CH₃),—N(CH₃)(CH₂CH₂CH₃), and —N(CH₂CH₃)(CH₂CH₂CH₃), as well as —N(CH₃)₂,—N(CH₂CH₃)₂, and —N(CH₂CH₂CH₃)₂.

The term “in purified form,” as used herein, refers to the physicalstate of a compound after the compound is isolated from a syntheticprocess (e.g., from a reaction mixture), a natural source, or acombination thereof. The term “in purified form,” also refers to thephysical state of a compound after the compound is obtained from apurification process or processes described herein or well-known to theskilled artisan (e.g., chromatography, recrystallization and the like),in sufficient purity to be characterizable by standard analyticaltechniques described herein or well-known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

The compounds of Formula (I) may contain one or more stereogenic centersand can thus occur as racemates, racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. Additionalasymmetric centers may be present depending upon the nature of thevarious substituents on the molecule. Each such asymmetric center willindependently produce two optical isomers and it is intended that all ofthe possible optical isomers and diastereomers in mixtures and as pureor partially purified compounds are included within the ambit of thisinvention. Any formulas, structures or names of compounds described inthis specification that do not specify a particular stereochemistry aremeant to encompass any and all existing isomers as described above andmixtures thereof in any proportion. When stereochemistry is specified,the invention is meant to encompass that particular isomer in pure formor as part of a mixture with other isomers in any proportion.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula (I) may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula (I) may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts andsolvates of the compounds as well as the salts, solvates and esters ofthe prodrugs), such as those which may exist due to asymmetric carbonson various substituents, including enantiomeric forms (which may existeven in the absence of asymmetric carbons), rotameric forms,atropisomers, and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers,or may be admixed, for example, as racemates or with all other, or otherselected, stereoisomers. The chiral centers of the present invention canhave the S or R configuration as defined by the IUPAC 1974Recommendations.

The compounds of Formula (I) can form salts which are also within thescope of this invention. Reference to a compound of Formula (I) hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula (I) contains both a basic moiety, such as, but not limited toa pyridine or imidazole, and an acidic moiety, such as, but not limitedto a carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Such acidic and basicsalts used within the scope of the invention are pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts. Salts ofthe compounds of Formula (I) may be formed, for example, by reacting acompound of Formula (I) with an amount of acid or base, such as anequivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,), 1-hydroxy-2-naphthoates(also known as xinafoates) and the like. Additionally, acids which aregenerally considered suitable for the formation of pharmaceuticallyuseful salts from basic pharmaceutical compounds are discussed, forexample, by P. Stahl et al, Camille G. (eds.) Handbook of PharmaceuticalSalts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Bergeet al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould,International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, ThePractice of Medicinal Chemistry (1996), Academic Press, New York; and inThe Orange Book (Food & Drug Administration, Washington, D.C. on theirwebsite). These disclosures are incorporated herein by reference.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

The present invention further includes the compounds of Formula (I) inall their isolated forms. For example, the above-identified compoundsare intended to encompass all forms of the compounds such as, anysolvates, hydrates, stereoisomers, and tautomers thereof.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

In the compounds of generic Formula (I), the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominantly found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofgeneric Formula (I). For example, different isotopic forms of hydrogen(H) include protium (¹H) and deuterium (²H). Protium is the predominanthydrogen isotope found in nature. Enriching for deuterium may affordcertain therapeutic advantages, such as increasing in vivo half-life orreducing dosage requirements, or may provide a compound useful as astandard for characterization of biological samples.Isotopically-enriched compounds within generic Formula (I) can beprepared without undue experimentation by conventional techniques wellknown to those skilled in the art or by processes analogous to thosedescribed in the examples herein using appropriate isotopically-enrichedreagents and/or intermediates.

Compounds of the Invention

The present invention provides a compound of Formula (I) or apharmaceutically acceptable salt thereof, wherein R¹, R³, R⁵, R⁶, A, Cyand the subscripts r, s, and t are as set forth below. Described beloware embodiments of the compound of Formula (I).

In embodiment no. 1, the invention provides a compound of the Formula(I),

-   or a pharmaceutically acceptable salt thereof, wherein-   ring A is a 5-membered heteroaryl containing 1 to 2 additional    heteroatoms independently selected from the group consisting of N,    O, and S;-   R¹ is selected from the group consisting of:    -   (a) C₁-C₃ alkyl;    -   (b) C₁-C₃ fluoroalkyl;    -   (c) C₁-C₃ alkoxy;    -   (d) C₃-C₆ cycloalkyl;    -   (e) phenyl;    -   (f) benzyl; and    -   (g) —C(O)N(C₁-C₃ alkyl)₂;-   R³ is selected from the group consisting of    -   (a) H;    -   (b) C₁-C₃ alkyl;    -   (c) C₁-C₃ alkoxy; and    -   (d) halo;-   ring C^(y) is a mono- or bicyclic carbocyclic ring system containing    4 to 12 carbon atoms;-   R⁵ is —C(O)OR^(A) or —C(O)NH₂;-   R⁶ is C₁-C₃ alkyl or halo;-   the subscript r is 0, 1, or 2;-   the subscript s is 0 or 1;-   the subscript t is 0, 1, 2, 3, 4, or 5;

R^(A) is independently selected from the group consisting of:

-   -   (a) H;    -   (b) C₁-C₈ alkyl;    -   (c) a group of the formula -M-R^(CH), wherein        -   M is a bond or —(CH₂)_(n1)—, wherein the subscript n1 is 1            or 2;        -   R^(CH) is (a) aryl or C₃-C₆ cycloalkyl optionally            substituted with 1-3 groups independently selected from            halo, C₁-C₄ alkyl, or C₁-C₄ alkoxy; or (b) a 5- to            6-membered monocyclic heterocycle containing 1 or 2            heteroatoms independently selected from the group consisting            of N and O, wherein said heterocycle of R^(CH) is optionally            substituted with 1 or 2 groups independently selected from            the group consisting of oxo and C₁₋₃ alkyl;    -   (d) a group of the formula —(CH₂)_(n1)—R^(m) or        —(CH₂)₂—O—(CH₂)₂—R^(m) wherein        -   R^(m) is —CO₂R^(m1), —C(O)N(R^(m2))₂, or —O(CO)R^(m1);            -   R^(m1) is C₁-C₄ alkyl; and            -   R^(m2) is H or C₁-C₄ alkyl;    -   (e) a group of the formula —(CH₂)₂—R^(n),        -   R^(n) is —OH, —O—(C₁-C₄ alkyl), —O—(CH₂)₂—O—(C₁-C₄ alkyl),            —NH₂, —N(H)(C₁-C₄ alkyl) or —N(C₁-C₄ alkyl)₂;    -   (f) a group of the formula

-   -    wherein        -   R^(o) is H or C₁-C₄ alkyl; and        -   R^(p) is C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or phenyl; and,    -   (g) a group of the formula

-   -    wherein R^(o) and R^(p) are as set forth above.

In embodiment no. 2, the invention provides a compound of the Formula(I), wherein ring A is selected from the group consisting of:

and R¹, the subscript r and the remaining variables are as set forth inembodiment no. 1.

In embodiment no. 3, the invention provides a compound of the Formula(I), wherein R¹ is selected from the group consisting of methyl, ethyl,n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, phenyl, andbenzyl; and the subscript r is 1; and the remaining variables are as setforth in embodiment no. 1.

In embodiment no. 4, the invention provides a compound of the Formula(I), wherein ring A is selected from the group consisting of:

and the remaining variables are as set forth in embodiment no. 1.

In embodiment no. 5, the invention provides a compound of the Formula(I), wherein R³ is H or methyl, and the remaining variables are as setforth in embodiment no. 1.

In embodiment no. 6, the invention provides a compound of the Formula(I) wherein

-   -   R¹ is selected from the group consisting of methyl, ethyl,        n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl,        phenyl, and benzyl;    -   the subscript r is 1;    -   R³ is methyl; and        the remaining variables are as set forth in embodiment no. 1.

In embodiment no. 7, the invention provides a compound of the Formula(I) wherein C^(y) is cyclobutyl or cyclohexyl and the remainingvariables are as set forth in embodiment no. 1.

In embodiment no. 8, the invention provides a compound of the Formula(I) wherein C^(y) is cyclobutyl and the subscripts s and t are both 0,and the remaining variables are as set forth in embodiment no. 1.

In embodiment no. 9, the invention provides a compound of the Formula(I) wherein

C^(y) is cyclohexyl;

R⁵ is —C(O)OR^(A);

R⁶ is methyl;

the subscript s is 1;

the subscript t is 0, 1, or 2; and

the remaining variable are as set forth in embodiment no. 1.

In embodiment no. 10, the invention provides a compound of the Formula(I) wherein R⁵ is —C(O)OR^(A), and the remaining variables are as setforth in any one of embodiment nos. 1-7 and 9. In one aspect ofembodiment no. 10, R^(A) is H.

In embodiment no. 11, the invention provides a compound selected fromany one of Examples 1-2.

In embodiment no. 12, the invention provides a compound selected fromthe group consisting of:

-   tert-butyl    4-hydroxy-4-(5-(3-methyl-5-((1-methyl-1H-1,2,4-triazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexanecarboxylate;-   4-hydroxy-4-(5-(3-methyl-5-((1-methyl-1H-1,2,4-triazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexanecarboxylic    acid;-   tert-butyl    4-(5-(3-((1-ethyl-1H-1,2,4-triazol-3-yl)amino)-5-methylphenyl)thiazol-2-yl)-4-hydroxycyclohexanecarboxylate;-   4-(5-(3-((1-ethyl-1H-1,2,4-triazol-3-yl)amino)-5-methylphenyl)thiazol-2-yl)-4-hydroxycyclohexanecarboxylic    acid;-   4-(5-(3-((1-ethyl-1H-1,2,4-triazol-3-yl)amino)-5-methylphenyl)thiazol-2-yl)-4-hydroxycyclohexanecarboxamide;-   1-{5-[3-methyl-5-(1H-pyrazol-3-ylamino)phenyl]-1,3-thiazol-2-yl}cyclobutanol;-   1-(5-{3-methyl-5-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutanol;-   1-(5-{3-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol;-   1-(5-{3-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol;-   1-(5-{3-methyl-5-[(3-methyl-1,2,4-thiadiazol-5-yl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutanol;-   1-(5-{3-methyl-5-[(5-methyl-1H-1,2,4-triazol-3-yl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutanol;-   1-(5-{3-methyl-5-[(1-methyl-1H-1,2,4-triazol-3-yl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutanol;-   1-[5-(3-methyl-5-{[1-(1-methylethyl)-1H-1,2,4-triazol-3-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutanol;-   1-(5-{3-[(1-ethyl-1H-1,2,4-triazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol;-   1-(5-{3-methyl-5-[(1-propyl-1H-1,2,4-triazol-3-yl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutanol;-   1-(5-{3-methyl-5-[(1-phenyl-1H-1,2,4-triazol-3-yl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutanol;-   3-({3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}amino)-N,N-dimethyl-1H-1,2,4-triazole-1-carboxamide;-   1-(5-{3-[(1-cyclohexyl-1H-1,2,4-triazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol;-   1-(5-{3-[(1-cyclobutyl-1H-1,2,4-triazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol;-   1-(5-{3-[(1-cyclobutyl-1H-1,2,4-triazol-5-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol;-   1-(5-{3-[(1-benzyl-1H-1,2,4-triazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol;-   tert-butyl cis-4-hydroxy-4-[5-(3-methyl-5-{[    1-(1-methylethyl)-1H-1,2,4-triazol-3-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate;-   cis-4-(5-{3-[(1-cyclobutyl-1H-1,2,4-triazol-5-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxycyclohexanecarboxylic    acid;-   cis-4-hydroxy-4-[5-(3-methyl-5-{[1-(1-methylethyl)-1H-1,2,4-triazol-3-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic    acid;-   cis-4-hydroxy-4-[5-(3-methyl-5-{[1-(1-methylethyl)-1H-1,2,4-triazol-3-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxamide;-   (1R,4S)-4-(5-{3-[(1-cyclobutyl-1H-1,2,4-triazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic    acid; and-   (1S,4R)-4-(5-{3-[(1-cyclobutyl-1H-1,2,4-triazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic    acid;    or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of Formula (I) or apharmaceutically acceptable salt thereof in purified form.

Uses of the Compounds

Compounds of Formula (I) or its pharmaceutically acceptable salts andpharmaceutical compositions containing such compounds can be used totreat or prevent a variety of conditions or diseases mediated by Spleentyrosine kinase (Syk). Such conditions and diseases include, but are notlimited to: (1) arthritis, including rheumatoid arthritis, juvenilearthritis, psoriatic arthritis and osteoarthritis; (2) asthma and otherobstructive airways diseases, including chronic asthma, late asthma,severe asthma, asthma exacerbations, airway hyper-responsiveness,bronchitis, bronchial asthma, allergic asthma, intrinsic asthma,extrinsic asthma, dust asthma, adult respiratory distress syndrome,recurrent airway obstruction, and chronic obstruction pulmonary diseaseincluding emphysema; (3) autoimmune diseases or disorders, includingthose designated as single organ or single cell-type autoimmunedisorders, for example Hashimoto's thyroiditis, autoimmune hemolyticanemia, autoimmune atrophic gastritis of pernicious anemia, autoimmuneencephalomyelitis, autoimmune orchitis, Goodpasture's disease,autoimmune thrombocytopenia including idiopathic thrombopenic purpura,sympathetic ophthalmia, myasthenia gravis, Graves' disease, primarybiliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis andmembranous glomerulopathy, those designated as involving systemicautoimmune disorder, for example systemic lupus erythematosis, immunethrombocytopenic purpura, rheumatoid arthritis, Sjogren's syndrome,Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis,polyarteritis nodosa, multiple sclerosis and bullous pemphigoid, andadditional autoimmune diseases, which can be B-cell (humoral) based orT-cell based, including Cogan's syndrome, ankylosing spondylitis,Wegener's granulomatosis, autoimmune alopecia, Type I or juvenile onsetdiabetes, and thyroiditis; (4) cancers or tumors, includingalimentary/gastrointestinal tract cancer, colon cancer, liver cancer,skin cancer including mast cell tumor and squamous cell carcinoma,breast and mammary cancer, ovarian cancer, prostate cancer, lymphoma andleukemia (including but not limited to acute myelogenous leukemia,chronic myelogenous leukemia, mantle cell lymphoma, NHL B cell lymphomas(e.g., precursor B-ALL, marginal zone B cell lymphoma, chroniclymphocytic leukemia, diffuse large B cell lymphoma, Burkitt lymphoma,mediastinal large B-cell lymphoma), Hodgkin lymphoma, NK and T celllymphomas; TEL-Syk and ITK-Syk fusion driven tumors) myelomas includingmultiple myeloma, myeloproliferative disorders kidney cancer, lungcancer, muscle cancer, bone cancer, bladder cancer, brain cancer,melanoma including oral and metastatic melanoma, Kaposi's sarcoma,proliferative diabetic retinopathy, and angiogenic-associated disordersincluding solid tumors, and pancreatic cancer; (5) diabetes, includingType I diabetes and complications from diabetes; (6) eye diseases,disorders or conditions including autoimmune diseases of the eye,keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitisassociated with Behcet's disease and lens-induced uveitis, keratitis,herpetic keratitis, conical keratitis, corneal epithelial dystrophy,keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave'sophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitissicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrineophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, andocular neovascularization; (7) intestinal inflammations, allergies orconditions including Crohn's disease and/or ulcerative colitis,inflammatory bowel disease, coeliac diseases, proctitis, eosinophilicgastroenteritis, and mastocytosis; (8) neurodegenerative diseasesincluding motor neuron disease, Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, Huntington's disease, cerebralischemia, or neurodegenerative disease caused by traumatic injury,strike, glutamate neurotoxicity or hypoxia; ischemic/reperfusion injuryin stroke, myocardial ischemica, renal ischemia, heart attacks, cardiachypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia; (9)platelet aggregation and diseases associated with or caused by plateletactivation, such as arteriosclerosis, thrombosis, intimal hyperplasiaand restenosis following vascular injury; (10) conditions associatedwith cardiovascular diseases, including restenosis, acute coronarysyndrome, myocardial infarction, unstable angina, refractory angina,occlusive coronary thrombus occurring post-thrombolytic therapy orpost-coronary angioplasty, a thrombotically mediated cerebrovascularsyndrome, embolic stroke, thrombotic stroke, transient ischemic attacks,venous thrombosis, deep venous thrombosis, pulmonary embolus,coagulopathy, disseminated intravascular coagulation, thromboticthrombocytopenic purpura, thromboangiitis obliterans, thrombotic diseaseassociated with heparin-induced thrombocytopenia, thromboticcomplications associated with extracorporeal circulation, thromboticcomplications associated with instrumentation such as cardiac or otherintravascular catheterization, intra-aortic balloon pump, coronary stentor cardiac valve, conditions requiring the fitting of prostheticdevices, and the like; (11) skin diseases, conditions or disordersincluding atopic dermatitis, eczema, psoriasis, scleroderma, pruritusand other pruritic conditions; (12) allergic reactions includinganaphylaxis, allergic rhinitis, allergic dermatitis, allergic urticaria,angioedema, allergic asthma, or allergic reaction to insect bites, food,drugs, or pollen; (13) transplant rejection, including pancreas islettransplant rejection, bone marrow transplant rejection,graft-versus-host disease, organ and cell transplant rejection such asbone marrow, cartilage, cornea, heart, intervertebral disc, islet,kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin,small intestine, or trachea, and xeno transplantation; (14) low gradescarring including scleroderma, increased fibrosis, cystic fibrosis,keloids, post-surgical scars, pulmonary fibrosis, vascular spasms,migraine, reperfusion injury, and post-myocardial infarction.

The invention thus provides compounds of Formula (I) andpharmaceutically acceptable salts thereof for use in therapy, andparticularly in the treatment of diseases and conditions mediated byinappropriate Syk activity. The inappropriate Syk activity referred toherein is any Syk activity that deviates from the normal Syk activityexpected in a particular patient. Inappropriate Syk activity may takethe form of, for instance, an abnormal increase in activity, or anaberration in the timing and or control of Syk activity. Suchinappropriate activity may result then, for example, from overexpressionor mutation of the protein kinase leading to inappropriate oruncontrolled activation.

In a further embodiment, the present invention is directed to methods ofregulating, modulating, or inhibiting Syk for the prevention and/ortreatment of disorders related to unregulated Syk activity.

In a further embodiment, the present invention provides a method oftreatment of a patient suffering from a disorder mediated by Sykactivity, which comprises administering to said patient an effectiveamount of a compound of Formula (I) or a pharmaceutically acceptablesalt, solvate, or a physiologically functional derivative thereof. In afurther embodiment, the present invention provides for the use of acompound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, or a physiologically functional derivative thereof, inthe preparation of a medicament for the treatment of a disorder mediatedby Syk activity.

In a further embodiment said disorder mediated by Syk activity isasthma. In a further embodiment said disorder is rheumatoid arthritis.In yet another embodiment, said disorder is cancer. In a furtherembodiment said disorder is ocular conjunctivitis.

Yet another aspect of the present invention provides a method fortreating diseases caused by or associated with Fc receptor signalingcascades, including FceRI and/or FcgRI-mediated degranulation as atherapeutic approach towards the treatment or prevention of diseasescharacterized by, caused by and/or associated with the release orsynthesis of chemical mediators of such Fc receptor signaling cascadesor degranulation. In addition, Syk is known to play a critical role inimmunotyrosine-based activation motif (ITAM) signaling, B cell receptorsignaling, T cell receptor signaling and is an essential component ofintegrin beta (1), beta (2), and beta (3) signaling in neutrophils.Thus, compounds of the present invention can be used to regulate Fcreceptor, ITAM, B cell receptor and integrin signaling cascades, as wellas the cellular responses elicited through these signaling cascades.Non-limiting examples of cellular responses that may be regulated orinhibited include respiratory burst, cellular adhesion, cellulardegranulation, cell spreading, cell migration, phagocytosis, calcium ionflux, platelet aggregation and cell maturation.

Compositions and Administration

While it is possible that, for use in therapy, a compound of Formula(I), as well as pharmaceutically acceptable salts thereof, may beadministered as the raw chemical, it is possible to present the activeingredient as a pharmaceutical composition. Accordingly, the inventionfurther provides a pharmaceutical composition, which comprises acompound of Formula (I) and pharmaceutically acceptable salts thereof,and a pharmaceutically acceptable carrier. The compounds of the Formula(I) and pharmaceutically acceptable salts thereof, are as describedabove. The carriers must be acceptable in the sense of being compatiblewith the other ingredients of the formulation and not deleterious to therecipient thereof. In accordance with another aspect of the inventionthere is also provided a process for the preparation of a pharmaceuticalcomposition including admixing a compound of the Formula (I), or apharmaceutically acceptable salt thereof, with one or morepharmaceutically acceptable carriers.

Pharmaceutical compositions of the present invention may be presented inunit dose forms containing a predetermined amount of active ingredientper unit dose. Such a unit may contain, for example, 5 μg to 1 g,preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compoundof the Formula (I), depending on the condition being treated, the routeof administration and the age, weight and condition of the patient. Suchunit doses may therefore be administered more than once a day. Preferredunit dosage compositions are those containing a daily dose or sub-dose(for administration more than once a day), as herein above recited, oran appropriate fraction thereof, of an active ingredient. Furthermore,such pharmaceutical compositions may be prepared by any of the methodswell known in the pharmacy art.

Pharmaceutical compositions of the present invention may be adapted foradministration by any appropriate route, for example by the oral(including buccal or sublingual), rectal, topical, inhaled, nasal,ocular, or parenteral (including intravenous and intramuscular) route.Such compositions may be prepared by any method known in the art ofpharmacy, for example by bringing into association the active ingredientwith the carrier(s) or excipient(s). Dosage forms include tablets,troches, dispersions, suspensions, solutions, capsules, creams,ointments, aerosols, and the like.

In a further embodiment, the present invention provides a pharmaceuticalcomposition adapted for administration by the oral route, for treating,for example, rheumatoid arthritis.

In a further embodiment, the present invention provides a pharmaceuticalcomposition adapted for administration by the nasal route, for treating,for example, allergic rhinitis.

In a further embodiment, the present invention provides a pharmaceuticalcomposition adapted for administration by the inhaled route, fortreating, for example, asthma, COPD or ARDS.

In a further embodiment, the present invention provides a pharmaceuticalcomposition adapted for administration by the ocular route, fortreating, diseases of the eye, for example, conjunctivitis.

In a further embodiment, the present invention provides a pharmaceuticalcomposition adapted for administration by the parenteral (includingintravenous) route, for treating, for example, cancer.

Pharmaceutical compositions of the present invention which are adaptedfor oral administration may be presented as discrete units such ascapsules or tablets; powders or granules; solutions or suspensions inaqueous or non-aqueous liquids; edible foams or whips; or oil-in-waterliquid emulsions or water-in-oil liquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Where appropriate, dosage unit compositions for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release, for example, by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of Formula (I) and pharmaceutically acceptable saltsthereof can also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesiclesand multilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of Formula (I) and pharmaceutically acceptable saltsthereof may also be delivered by the use of monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Thecompounds may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels.

Dosage forms for inhaled administration may conveniently be formulatedas aerosols or dry powders.

For compositions suitable and/or adapted for inhaled administration, itis preferred that the compound or salt of Formula (I) is in aparticle-size-reduced form, and more preferably the size-reduced form isobtained or obtainable by micronisation. The preferable particle size ofthe size-reduced (e.g., micronised) compound or salt or solvate isdefined by a D50 value of about 0.5 to about 10 microns (for example asmeasured using laser diffraction).

Aerosol formulations, e.g., for inhaled administration, can comprise asolution or fine suspension of the active substance in apharmaceutically acceptable aqueous or non-aqueous solvent. Aerosolformulations can be presented in single or multidose quantities insterile form in a sealed container, which can take the form of acartridge or refill for use with an atomising device or inhaler.Alternatively the sealed container may be a unitary dispensing devicesuch as a single dose nasal inhaler or an aerosol dispenser fitted witha metering valve (metered dose inhaler) which is intended for disposalonce the contents of the container have been exhausted.

Where the dosage form comprises an aerosol dispenser, it preferablycontains a suitable propellant under pressure such as compressed air,carbon dioxide or an organic propellant such as a hydrofluorocarbon(HFC). Suitable HFC propellants include 1,1,1,2,3,3,3-heptafluoropropaneand 1,1,1,2-tetrafluoroethane. The aerosol dosage forms can also takethe form of a pump-atomiser. The pressurised aerosol may contain asolution or a suspension of the active compound. This may require theincorporation of additional excipients e.g., co-solvents and/orsurfactants to improve the dispersion characteristics and homogeneity ofsuspension formulations. Solution formulations may also require theaddition of co-solvents such as ethanol. Other excipient modifiers mayalso be incorporated to improve, for example, the stability and/or tasteand/or fine particle mass characteristics (amount and/or profile) of theformulation.

For pharmaceutical compositions suitable and/or adapted for inhaledadministration, it is preferred that the pharmaceutical composition is adry powder inhalable composition. Such a composition can comprise apowder base such as lactose, glucose, trehalose, mannitol or starch, thecompound of Formula (I) or salt or solvate thereof (preferably inparticle-size-reduced form, e.g., in micronised form), and optionally aperformance modifier such as L-leucine or another amino acid, and/ormetals salts of stearic acid such as magnesium or calcium stearate.Preferably, the dry powder inhalable composition comprises a dry powderblend of lactose and the compound of Formula (I) or salt thereof. Thelactose is preferably lactose hydrate e.g., lactose monohydrate and/oris preferably inhalation-grade and/or fine-grade lactose. Preferably,the particle size of the lactose is defined by 90% or more (by weight orby volume) of the lactose particles being less than 1000 microns(micrometers) (e.g., 10-1000 microns e.g., 30-1000 microns) in diameter,and/or 50% or more of the lactose particles being less than 500 microns(e.g., 10-500 microns) in diameter. More preferably, the particle sizeof the lactose is defined by 90% or more of the lactose particles beingless than 300 microns (e.g., 10-300 microns e.g., 50-300 microns) indiameter, and/or 50% or more of the lactose particles being less than100 microns in diameter. Optionally, the particle size of the lactose isdefined by 90% or more of the lactose particles being less than 100-200microns in diameter, and/or 50% or more of the lactose particles beingless than 40-70 microns in diameter. It is preferable that about 3 toabout 30% (e.g., about 10%) (by weight or by volume) of the particlesare less than 50 microns or less than 20 microns in diameter. Forexample, without limitation, a suitable inhalation-grade lactose isE9334 lactose (10% fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017J D Zwolle, Netherlands).

Optionally, in particular for dry powder inhalable compositions, apharmaceutical composition for inhaled administration can beincorporated into a plurality of sealed dose containers (e.g.,containing the dry powder composition) mounted longitudinally in a stripor ribbon inside a suitable inhalation device. The container isrupturable or peel-openable on demand and the dose of e.g., the drypowder composition can be administered by inhalation via the device suchas the DISKUS® device (GlaxoSmithKline). Other dry powder inhalers arewell known to those of ordinary skill in the art, and many such devicesare commercially available, with representative devices includingAerolizer® (Novartis), Airmax™ (IVAX), ClickHaler® (Innovata Biomed),Diskhaler® (GlaxoSmithKline), Accuhaler (GlaxoSmithKline), Easyhaler®(Orion Pharma), Eclipse™ (Aventis), FlowCaps® (Hovione), Handihaler®(Boehringer Ingelheim), Pulvinal® (Chiesi), Rotahaler®(GlaxoSmithKline), SkyeHaler™ or Certihaler™ (SkyePharma), Twisthaler(Schering Corporation), Turbuhaler® (AstraZeneca), Ultrahaler®(Aventis), and the like.

Dosage forms for ocular administration may be formulated as solutions orsuspensions with excipients suitable for ophthalmic use.

Dosage forms for nasal administration may conveniently be formulated asaerosols, solutions, drops, gels or dry powders.

Pharmaceutical compositions adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurised aerosols, nebulizers orinsufflators.

For pharmaceutical compositions suitable and/or adapted for intranasaladministration, the compound of Formula (I) or a pharmaceuticallyacceptable salt or solvate thereof may be formulated as a fluidformulation for delivery from a fluid dispenser. Such fluid dispensersmay have, for example, a dispensing nozzle or dispensing orifice throughwhich a metered dose of the fluid formulation is dispensed upon theapplication of a user-applied force to a pump mechanism of the fluiddispenser. Such fluid dispensers are generally provided with a reservoirof multiple metered doses of the fluid formulation, the doses beingdispensable upon sequential pump actuations. The dispensing nozzle ororifice may be configured for insertion into the nostrils of the userfor spray dispensing of the fluid formulation into the nasal cavity. Afluid dispenser of the aforementioned type is described and illustratedin WO-A-2005/044354, the entire content of which is hereby incorporatedherein by reference. The dispenser has a housing which houses a fluiddischarge device having a compression pump mounted on a container forcontaining a fluid formulation. The housing has at least onefinger-operable side lever which is movable inwardly with respect to thehousing to cam the container upwardly in the housing to cause the pumpto compress and pump a metered dose of the formulation out of a pumpstem through a nasal nozzle of the housing. A particularly preferredfluid dispenser is of the general type illustrated in FIGS. 30-40 ofWO-A-2005/044354.

The following are examples of representative pharmaceutical dosage formsfor the compounds of this invention:

Injectable Suspension (I.M.) mg/mL Compound of Formula (I) 10Methylcellulose 5.0 Tween 80 0.5 Benzyl alcohol 9.0 Benzalkoniumchloride 1.0 Water for injection to a total volume of 1 mL

Tablet mg/tablet Compound of Formula (I) 25 Microcrystalline Cellulose415 Providone 14.0 Pregelatinized Starch 43.5 Magnesium Stearate 2.5 500

Capsule mg/capsule Compound of Formula (I) 25 Lactose Powder 573.5Magnesium Stearate 1.5 600

Aerosol Per canister Compound of Formula (I)   24 mg Lecithin, NF LiquidConcentrate  1.2 mg Trichlorofluoromethane, NF 4.025 gmDichlorodifluoromethane, NF 12.15 gm

It will be appreciated that when the compound of the present inventionis administered in combination with other therapeutic agents normallyadministered by the inhaled, intravenous, oral or intranasal route, thatthe resultant pharmaceutical composition may be administered by the sameroutes.

It should be understood that in addition to the ingredients particularlymentioned above, the compositions may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavouringagents.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors including, for example,the age and weight of the animal, the precise condition requiringtreatment and its severity, the nature of the formulation, and the routeof administration, and will ultimately be at the discretion of theattendant physician or veterinarian. However, an effective amount of acompound of Formula (I) for the treatment of diseases or conditionsassociated with inappropriate Syk activity, will generally be in therange of 5 μg to 100 mg/kg body weight of recipient (patient) per dayand more usually in the range of 5 μg to 10 mg/kg body weight per day.This amount may be given in a single dose per day or more usually in anumber (such as two, three, four, five or six) of sub-doses per day suchthat the total daily dose is the same. An effective amount of a salt orsolvate, thereof, may be determined as a proportion of the effectiveamount of the compound of Formula (I) per se.

The compositions of the invention can further comprise one or moreadditional therapeutic agents, as discussed in further detail below.Accordingly, in one embodiment, the present invention providescompositions comprising: (i) a compound of Formula (I) or apharmaceutically acceptable salt thereof; (ii) one or more additionaltherapeutic agents, that are not compounds of Formula (I); and (iii) apharmaceutically acceptable carrier, wherein the amounts in thecomposition are together effective to treat one of the disease orconditions discussed above.

Combination Therapy

The compounds of Formula (I) or their pharmaceutically acceptable saltsmay be used in combination, either in a single formulation orco-administered as separate formulations with at least one additionaltherapeutic agent to treat or prevent the diseases and conditionsdescribed herein. For the treatment of the inflammatory diseases,rheumatoid arthritis, psoriasis, inflammatory bowel disease, COPD,asthma and allergic rhinititis, these additional therapeutic agentsinclude, but are not limited to: (1) TNF-α inhibitors such as infliximab(Remicade®), etanercept (Enbrel®), adalimumab (Humira®), certolizumabpegol (Cimzia®), and golimumab (Simponi®); (2) non-selective COX-I/COX-2inhibitors (such as piroxicam, diclofenac, propionic acids such asnaproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamatessuch as mefenamic acid, indomethacin, sulindac, etodolac, azapropazone,pyrazolones such as phenylbutazone, salicylates such as aspirin); (3)COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxiband etoricoxib); (4) other agents for treatment of rheumatoid arthritisincluding methotrexate, leflunomide, sulfasalazine, azathioprine,cyclosporin, tacrolimus, penicillamine, bucillamine, actarit,mizoribine, lobenzarit, ciclesonide, hydroxychloroquine,d-penicillamine, aurothiomalate, auranofin or parenteral or oral gold,cyclophosphamide, Lymphostat-B, BAFF/APRIL inhibitors and CTLA-4-Ig ormimetics thereof; (5) leukotriene biosynthesis inhibitor, 5-lipoxygenase(5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonistsuch as zileuton; (6) LTD4 receptor antagonist such as zafirlukast,montelukast and pranlukast; (7) PDE4 inhibitor such as roflumilast,cilomilast, AWD-12-281 (Elbion), and PD-168787 (Pfizer); (8)antihistaminic H1 receptor antagonists such as cetirizine,levocetirizine, loratadine, desloratadine, fexofenadine, astemizole,azelastine, levocabastine, olopatidine, methapyrilene andchlorpheniramine; (9) α1- and α2-adrenoceptor agonist vasoconstrictorsympathomimetic agent, such as propylhexedrine, phenylephrine,phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride,oxymetazoline hydrochloride, tetrahydrozoline hydrochloride,xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride;(10) anticholinergic agents such as ipratropium bromide, tiotropiumbromide, oxitropium bromide, aclidinium bromide, glycopyrrolate,(R,R)-glycopyrrolate, pirenzepine, and telenzepine; (11) β-adrenoceptoragonists such as metaproterenol, isoproterenol, isoprenaline, albuterol,formoterol (particularly the fumarate salt), salmeterol (particularlythe xinafoate salt), terbutaline, orciprenaline, bitolterol mesylate,fenoterol, and pirbuterol, or methylxanthanines including theophyllineand aminophylline, sodium cromoglycate; (12) insulin-like growth factortype I (IGF-1) mimetic; (13) glucocorticosteroids, especially inhaledglucocorticoid with reduced systemic side effects, such as prednisone,prednisolone, flunisolide, triamcinolone acetonide, beclomethasonedipropionate, budesonide, fluticasone propionate, ciclesonide andmometasone furoate; (14) kinase inhibitors such as inhibitors of theJanus Kinases (JAK 1 and/or JAK2 and/or JAK 3 and/or TYK2) such astofacitinib (Pfizer), baricitinib (Incyte), VX-509 (Vertex), ASP-015K(Astellas), GLPG0634 (Galapagos), SB-1578 (SBIO), and AC-430 (AmbitBiosciences); p38 MAPK and IKK2; (15) B-cell targeting biologics such asrituximab (Rituxan®); (16) selective costimulation modulators such asabatacept (Orencia); (17) interleukin inhibitors, such as IL-1 inhibitoranakinra (Kineret) and IL-6 inhibitor tocilizumab (Actemra).

The present invention also provides for so-called “triple combination”therapy, comprising a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof together with beta₂-adrenoreceptor agonist andan anti-inflammatory corticosteroid. Preferably this combination is fortreatment and/or prophylaxis of asthma, COPD or allergic rhinitis. Thebeta₂-adrenoreceptor agonist and/or the anti-inflammatory corticosteroidcan be as described above and/or as described in WO 03/030939 A1.Representative examples of such a “triple” combination are a compound ofFormula (I) or a pharmaceutically acceptable salt thereof in combinationwith the components of Advair® (salmeterol xinafoate and fluticasonepropionate), Symbicort® (budesonide and formoterol fumarate), or Dulera®(mometasone furoate and formoterol fumarate).

For the treatment of cancer a compound of Formula (I) may be combinedwith an one or more additional therapeutic agents which are anticanceragents. Examples of such agents can be found in Cancer Principles andPractice of Oncology by V. T. Devita and S. Hellman (editors), 6thedition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. Aperson of ordinary skill in the art would be able to discern whichcombinations of agents would be useful based on the particularcharacteristics of the drugs and the cancer involved. Such anticanceragents include, but are not limited to, the following: (1) an estrogenreceptor modulator such as diethylstibestral, tamoxifen, raloxifene,idoxifene, LY353381, LY117081, toremifene, fluoxymestero, and SH646; (2)other hormonal agents including aromatase inhibitors (e.g.,aminoglutethimide, tetrazole anastrozole, letrozole and exemestane),luteinizing hormone release hormone (LHRH) analogues, ketoconazole,goserelin acetate, leuprolide, megestrol acetate and mifepristone; (3)an androgen receptor modulator such as finasteride and other5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole,and abiraterone acetate; (4) a retinoid receptor modulator such asbexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide; (5) an antiproliferativeagent such as antisense RNA and DNA oligonucleotides such as G3139,ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such asenocitabine, carmofur, tegafur, pentostatin, doxifluridine,trimetrexate, fludarabine, capecitabine, galocitabine, cytarabineocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid,emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine,2′-deoxy-2′-methylidenecytidine, 2′-fluoromethylene-2′-deoxycytidine,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine, aminopterin, 5-fluorouracil,floxuridine, methotrexate, leucovarin, hydroxyurea, thioguanine (6-TG),mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate,cladribine (2-CDA), asparaginase, gemcitabine, alanosine, swainsonine,lometrexol, dexrazoxane, methioninase, and3-aminopyridine-2-carboxaldehyde thiosemicarbazone; (6) a prenyl-proteintransferase inhibitor including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase); (7) an HMG-CoA reductase inhibitor such as lovastatin,simvastatin, pravastatin, atorvastatin, fluvastatin and rosuvastatin;(8) an angiogenesis inhibitor such as inhibitors of the tyrosine kinasereceptors Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2), inhibitors ofepidermal-derived, fibroblast-derived, or platelet derived growthfactors, MMP (matrix metalloprotease) inhibitors, integrin blockers,interferon-α, interleukin-12, erythropoietin (epoietin-α),granulocyte-CSF (filgrastin), granulocyte, macrophage-CSF(sargramostim), pentosan polysulfate, cyclooxygenase inhibitors,steroidal anti-inflammatories, carboxyamidotriazole, combretastatin A-4,squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide,angiostatin, troponin-1, angiotensin II antagonists, heparin,carboxypeptidase U inhibitors, and antibodies to VEGF, endostatin,ukrain, ranpirnase, IM862, acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]-methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfatedmannopentaose phosphate, and3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416); (9) PPAR-γagonists, PPAR-δ agonists, thiazolidinediones (such as DRF2725, CS-011,troglitazone, rosiglitazone, and pioglitazone), fenofibrate,gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555,GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570,PNU182716, DRF552926,2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionicacid (disclosed in U.S. Ser. No. 09/782,856), and(2R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylicacid (disclosed in U.S. Ser. No. 60/235,708 and 60/244,697); (9) aninhibitor of inherent multidrug resistance including inhibitors ofp-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922,VX853 and PSC833 (valspodar); (10) an inhibitor of cell proliferationand survival signaling such as inhibitors of EGFR (for example gefitiniband erlotinib), inhibitors of ERB-2 (for example trastuzumab),inhibitors of IGF 1R such as MK-0646 (dalotuzumab), inhibitors of CD20(rituximab), inhibitors of cytokine receptors, inhibitors of MET,inhibitors of PI3K family kinase (for example LY294002),serine/threonine kinases (including but not limited to inhibitors of Aktsuch as described in (WO 03/086404, WO 03/086403, WO 03/086394, WO03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO 02/083138),inhibitors of Raf kinase (for example BAY-43-9006), inhibitors of MEK(for example CI-1040 and PD-098059) and inhibitors of mTOR (for exampleWyeth CCI-779 and Ariad AP23573); (11) a bisphosphonate such asetidronate, pamidronate, alendronate, risedronate, zoledronate,ibandronate, incadronate or cimadronate, clodronate, EB-1053,minodronate, neridronate, piridronate and tiludronate; (12) γ-secretaseinhibitors, (13) agents that interfere with receptor tyrosine kinases(RTKs) including inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met; (14) anagent that interferes with a cell cycle checkpoint including inhibitorsof ATR, ATM, the Chk1 and Chk2 kinases and cdk and cdc kinase inhibitorsand are specifically exemplified by 7-hydroxystaurosporin, flavopiridol,CYC202 (Cyclacel) and BMS-387032; (15) BTK inhibitors such as PCI32765,AVL-292 and AVL-101; (16) PARP inhibitors including iniparib, olaparib,AGO14699, ABT888 and MK4827; (16) ERK inhibitors; (17) mTOR inhibitorssuch as sirolimus, ridaforolimus, temsirolimus, everolimus; and (18)cytotoxic/cytostatic agents.

“Cytotoxic/cytostatic agents” refer to compounds which cause cell deathor inhibit cell proliferation primarily by interfering directly with thecell's functioning or inhibit or interfere with cell mytosis, includingalkylating agents, tumor necrosis factors, intercalators, hypoxiaactivatable compounds, microtubule inhibitors/microtubule-stabilizingagents, inhibitors of mitotic kinesins, inhibitors of histonedeacetylase, inhibitors of kinases involved in mitotic progression,antimetabolites; biological response modifiers; hormonal/anti-hormonaltherapeutic agents, haematopoietic growth factors, monoclonal antibodytargeted therapeutic agents, topoisomerase inhibitors, proteasomeinhibitors and ubiquitin ligase inhibitors.

Examples of cytotoxic agents include, but are not limited to, sertenef,cachectin, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine,melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine,streptozocin, tasonermin, lonidamine, carboplatin, altretamine,dacarbazine, procarbazine, prednimustine, dibromodulcitol, ranimustine,fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin,estramustine, improsulfan tosilate, trofosfamide, nimustine,dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin,cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine,glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,doxorubicin, daunorubicin, idarubicin, anthracenedione, bleomycin,mitomycin C, dactinomycin, plicatomycin, bisantrene, mitoxantrone,pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755, and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin.

An example of a hypoxia activatable compound is tirapazamine.

Examples of proteasome inhibitors include but are not limited tolactacystin and bortezomib.

Examples of microtubule inhibitors/microtubule-stabilising agentsinclude vincristine, vinblastine, vindesine, vinzolidine, vinorelbine,vindesine sulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine,podophyllotoxins (e.g., etoposide (VP-16) and teniposide (VM-26)),paclitaxel, docetaxol, rhizoxin, dolastatin, mivobulin isethionate,auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and6,288,237) and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin, lurtotecan,7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100,BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2-(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,and dimesna.

Examples of inhibitors of mitotic kinesins include, but are not limitedto inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E,inhibitors of MCAK, inhibitors of Kif14, inhibitors of Mphosph1 andinhibitors of Rab6-KIFL.

Examples of “histone deacetylase inhibitors” include, but are notlimited to, vorinostat, trichostatin A, oxamflatin, PXD101, MG98,valproic acid and scriptaid.

“Inhibitors of kinases involved in mitotic progression” include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK; in particular inhibitors of PLK-1), inhibitors of bub-1and inhibitors of bub-R1. An example of an “aurora kinase inhibitor” isVX-680.

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N6-[4-deoxy-4-[N2-[2,4-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine, aminopterin, 5-fluorouracil,floxuridine, methotrexate, leucovarin, hydroxyurea, thioguanine (6-TG),mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate,cladribine (2-CDA), asparaginase, gemcitabine, alanosine, swainsonine,lometrexol, dexrazoxane, methioninase, and3-aminopyridine-2-carboxaldehyde thiosemicarbazone.

Non-limiting examples of suitable additional therapeutic agents used incancer therapy that may be combined with compounds of Formula (I)include, but are not limited to, abarelix; aldesleukin; alemtuzumab;alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenictrioxide; asparaginase; azacitidine; bendamustine; bevacuzimab;bexarotene; bleomycin; bortezomib; busulfan; calusterone; capecitabine;carboplatin; carmustine; cetuximab; chlorambucil; cisplatin; cladribine;clofarabine; cyclophosphamide; cytarabine; dacarbazine; dactinomycin,actinomycin D; dalteparin; darbepoetin alfa; dasatinib; daunorubicin;degarelix; denileukin diftitox; dexrazoxane; docetaxel; doxorubicin;dromostanolone propionate; eculizumab; Elliott's B Solution;eltrombopag; epirubicin; epoetin alfa; erlotinib; estramustine;etoposide phosphate; etoposide; everolimus; exemestane; filgrastim;floxuridine; fludarabine; fluorouracil; fulvestrant; gefitinib;gemcitabine; gemtuzumab ozogamicin; goserelin acetate; histrelinacetate; hydroxyurea; ibritumomab tiuxetan; idarubicin; ifosfamide;imatinib mesylate; interferon alfa 2a; interferon alfa-2b; irinotecan;ixabepilone; lapatinib; lenalidomide; letrozole; leucovorin; leuprolideacetate; levamisole; lomustine; meclorethamine, nitrogen mustard;megestrol acetate; melphalan, L-PAM; mercaptopurine; mesna;methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone;nandrolone phenpropionate; nelarabine; nilotinib; Nofetumomab;ofatumumab; oprelvekin; oxaliplatin; paclitaxel; palifermin; pamidronat;panitumumab; pazopanib; pegademase; pegaspargase; Pegfilgrastim;pemetrexed disodium; pentostatin; pipobroman; plerixafor; plicamycin,mithramycin); porfimer sodium; pralatrexate; procarbazine; quinacrine;Rasburicase; raloxifene hydrochloride; Rituximab; romidepsin;romiplostim; sargramostim; sargramostim; satraplatin; sorafenib;streptozocin; sunitinib maleate; tamoxifen; temozolomide; temsirolimus;teniposide; testolactone; thioguanine; thiotepa; topotecan; toremifene;tositumomab; trastuzumab; tretinoin; uracil mustard; valrubicin;vinblastine; vincristine; vinorelbine; vorinostat; and zoledronate.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like.

These combinations are of particular interest in respiratory diseasesand are conveniently adapted for inhaled or intranasal delivery.

In one embodiment, the compound of Formula (I) is administered during atime when the additional therapeutic agent(s) exert their prophylacticor therapeutic effect, or vice versa.

In another embodiment, the compound of Formula (I) and the additionaltherapeutic agent(s) are administered in doses commonly employed whensuch agents are used as monotherapy for treating the disorder.

In another embodiment, the compound of Formula (I) and the additionaltherapeutic agent(s) are administered in doses lower than the dosescommonly employed when such agents are used as monotherapy for treatingthe disorder.

In one embodiment, the compound of Formula (I) and the additionaltherapeutic agent(s) are present in the same composition, which issuitable for oral administration.

The compound of Formula (I) and the additional therapeutic agent(s) canact additively or synergistically. A synergistic combination may allowthe use of lower dosages of one or more agents and/or less frequentadministration of one or more agents of a combination therapy. A lowerdosage or less frequent administration of one or more agents may lowertoxicity of the therapy without reducing the efficacy of the therapy.

The doses and dosage regimen of the additional therapeutic agent(s) usedin the combination therapies of the present invention for the treatmentor prevention of a disease or disorder can be determined by theattending clinician, taking into consideration the approved doses anddosage regimen in the package insert; the age, sex and general health ofthe patient; and the type and severity of the disease or conditionmediated by Syk.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of the compound of Formula (I) or a pharmaceuticallyacceptable salt of said compound, optionally at least one additionaltherapeutic agent listed above and a pharmaceutically acceptablecarrier, vehicle or diluent.

Methods of Preparing the Compounds of Formula (I)

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the Formula (I) are prepared in the Examples.

Compounds of general Formula (I) may be prepared by methods known in theart of organic synthesis as set forth in part by the following synthesisschemes. In all of the schemes described below, it is well understoodthat protecting groups for sensitive or reactive groups are employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (T. W. Green and P. G. M. Wuts (1991) ProtectingGroups in Organic Synthesis, John Wiley & Sons). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selection ofprotecting groups as well as the reaction conditions and order ofreaction steps shall be consistent with the preparation of compounds ofFormula (I). Those skilled in the art will recognize whether astereocenter exists in compounds of Formula (I). Accordingly, thepresent invention includes all possible stereoisomers and includes notonly mixtures of stereoisomers (such as racemic compounds) but theindividual stereoisomers as well. When a compound is desired as a singleenantiomer, it may be obtained by stereospecific synthesis or byresolution of the final product or any convenient intermediate.Resolution of the final product, an intermediate, or a starting materialmay be affected by any suitable method known in the art. See, forexample, Stereochemistry of Organic Compounds by E. L. Eliel, S. H.Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The following solvents, reagents, protecting groups, moieties, and otherdesignations may be referred to by their abbreviations:

Me=methyl; Et=ethyl; Pr=propyl; iPr=isopropyl, Bu=butyl;t-Bu=tert-butyl; Ph=phenyl, and Ac=acetyl

μl=microliters

AcOH or HOAc=acetic acid

ACN=acetonitrile

APCI=atmospheric-pressure chemical ionization

aq=aqueous

Bn=benzyl

Boc or BOC=tert-butoxycarbonyl

Bz=benzoyl

Boc=tert-butoxycarbonyl

Calc'd=calculated

Cbz=benyzloxycarbonyl

DCM=dichloromethane:

DMAP=4-dimethylaminopyridine

DIBAL=diisobutylaluminum hydride

DIEA or Hünig's Base=N,N-diisopropylethylamine

DMA=1,2-dimethylacetamide

DMF=dimethylformamide

DMSO=dimethyl sulfoxide

DTT=dithiothreitol

EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

EDTA=ethylenediamine tetraacetic acid

ESI=electrospray ionization

EtOAc=ethyl acetate

g=grams

GST=glutathione S-transferase

h=hour

HMDS=1,1,1,3,3,3-hexamethyldisilazane

HATU=N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate

HPLC=high-performance liquid chromatography

HOBt=1-hydroxybenzotriazole

LDA=lithium diisopropylamide

LCMS=liquid chromatography mass spectrometry

min=minute

mg=milligrams

mL=milliliters

mmol=millimoles

Me=methyl

MeOH: methanol

MS=mass spectrometry

NBS=N-bromosuccimide

NMR=nuclear magnetic resonance spectroscopy

Obsv'd=observed

rac=racemic mixture

RT or rt=room temperature (ambient, about 25° C.)

sat=saturated

SFC=supercritical fluid chromatography

TBSC1=t-butyldimethylsilyl chloride

TBS=t-butyldimethyl silyl

TEA=triethylamine (Et₃N)

TFA=trifluoroacetic acid

TFAA=trifluoroacetic anhydride

THF=tetrahydrofuran

TLC=thin layer chromatography

TMS=trimethylsilyl

Tris=tris(hydroxymethyl)aminomethane

General Methods

Compounds of the Formula (I) can be prepared according to one of thegeneral synthetic schemes procedures set forth in Schemes 1-5 below,and/or by methods similar to those described in the Examples below.

Compounds of Formula (I) are prepared by palladium-mediated coupling ofsubstituted amino A-rings (1) with bromo B-ring thiazoles (2).Alternatively, compounds of Formula (I) are obtained bypalladium-mediated coupling of bromo AB-rings (4) with substitutedthiazoles (5). Bromo AB-rings (4) are prepared by palladium mediatedcoupling of amino A-rings (1) with bis-bromo B-rings (3) or by acidcatalyzed S_(N)Ar of amino A-rings (1) with bis-bromo B-rings (3).

Compounds of formula (8) are prepared by deprotonating thiazolecompounds (6) with a strong base, such as LDA, and reacting theresultant species with an electrophile (7).

Carboxylic acids (10) are prepared by hydrolysis of alkyl esters (9).The resultant acids (10) also provide amides (11) under commonly usedcoupling conditions, such as carbodiimide-based coupling conditions.

As shown in Scheme 4, compounds of structural subtype (A) are preparedfrom the carboxylic acid (A1) by a Mitsunobu reaction with variousprimary and secondary alcohols. Compounds of structural subtype (B) areprepared by the alkylation of the carboxylic acid (A1) by alkyl halidesof formula (B1). Compounds of structural subtype (C) are prepared by thealkylation of the carboxylic acid (A1) by alkyl halides of formula (C1).

As shown in Scheme 5, compounds of structural subtype (D) are preparedby the reaction of the carboxylic acid (A1) withtrimethylsilyldiazomethane and methanol.

The starting materials and reagents used in preparing compoundsdescribed in the examples below are either available from commercialsuppliers or were prepared by literature methods known to those skilledin the art.

The examples below are being provided to further illustrate the presentinvention. The examples provided below are for illustrative purposesonly; the scope of the invention is not to be considered limited in anyway thereby.

Where mass spectral (MS) data are presented in the examples below,analysis was performed using an Agilent Technologies 6120 quadrupoleLC/MS. Resolution of enantiomers was typically performed usingsupercritical fluid chromatography utilizing a Chiral Technologiesstationary phase such as OJ-H or OJ column (stationary phase withparticle size of 5 or 10 micron) with a mobile phase of CO₂ and a loweralcohol such as methanol or isopropanol.

EXAMPLES Preparative Example 1—Preparation of Halo or Amino HeterocyclicPrecursors Preparative Examples 1.1 and1.2—1-Cyclobutyl-1H-1,2,4-triazol-3-amine and1-Cyclobutyl-1H-1,2,4-triazol-5-amine

1H-1,2,4-Triazol-3-amine (500 mg, 5.95 mmol) was taken up in methanol(15 mL) and sodium methoxide (338 mg, 5.95 mmol) was added. The mixturewas stirred at room temperature for 30 minutes and then bromocyclobutane(0.56 mL, 5.95 mmol) was added in one portion. The reaction was stirredat room temperature overnight and then heated to 80° C. for 6 hours. Theresulting mixture was cooled to room temperature and concentrated underreduced pressure. The residue was azeotroped with toluene (3×). Theresulting solid was slurried in boiling chloroform and filtered. Thefiltrate was concentrated under reduced pressure and then recrystallizedfrom boiling chloroform/hexanes to afford a mixture of1-cyclobutyl-1H-1,2,4-triazol-3-amine and1-cyclobutyl-1H-1,2,4-triazol-5-amine as an orange-yellow solid. MS ESIcalcd. for C₆H₁₁N₄ [M+H]⁺ 139. found 139.

Preparative Example 2—Preparation of Ketone C^(y) Precursers PreparativeExample 2.1—Methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate

Step 1:

Methyl 3-oxobutanoate (232 g, 2.00 mol) and paraformaldehyde (30 g, 999mmol) were combined and piperidine (10 g, 117.44 mmol) was added. Theresulting solution was stirred for 2 hours at 0° C. The solution wasthen heated to 60° C. for 2 hours. The mixture was extracted withdiethyl ether (3×), and the organic layers were combined and dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to afford dimethyl2-methyl-6-oxocyclohex-1-ene-1,3-dicarboxylate as a brown oil. MS ESIcalc'd. for C₁₁H₁₅O₅ [M+H]⁺ 227. found 227.

Step 2:

Dimethyl 2-methyl-6-oxocyclohex-1-ene-1,3-dicarboxylate (150 g, 663mmol) in methanol (150 mL) was added dropwise with stirring over 30minutes to a solution of sodium methanolate (90 g, 1.67 mol) in methanol(300 mL). The resulting solution was heated to 80° C. for 30 minutes,and the mixture was concentrated under reduced pressure. The reactionmixture was diluted with water/ice (120 mL), then diluted further withacetic acid (130 mL). The resulting solution was extracted with diethylether (3×), and the organic layers were combined and dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by distillation under reducedpressure (5 mm Hg), and the fraction was collected at 110-120° C. Methyl2-methyl-4-oxocyclohex-2-enecarboxylate was obtained as a yellow oil. MSESI calc'd. for C₉H₁₃O₃ [M+H]⁺ 169. found 169.

Step 3:

Copper iodide (121.8 g, 639.54 mmol) was suspended in diethyl ether (800mL). Methyllithium (1.6 M in diethyl ether, 800 mL, 1.28 mol) was addeddropwise at −40° C. over 3 hours. A solution of methyl2-methyl-4-oxocyclohex-2-enecarboxylate (53.8 g, 319.88 mmol) in diethylether (400 mL) was added at −40° C. over 2 minutes. The resultingsolution was stirred for 5 hours at −20° C. The mixture was diluted withsaturated aqueous ammonium chloride (2.5 L) and extracted with ethylacetate (3×2 L). The combined organic extracts were dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (ethylacetate/petroleum ether) to afford methyl2,2-dimethyl-4-oxocyclohexanecarboxylate as a yellow oil. MS ESI calc'd.for C₁₀H₁₇O₃ [M+H]⁺ 185. found 185. ¹H NMR (600 MHz, CDCl₃) δ 3.49 (s,3H), 2.43-2.40 (m, 1H), 2.35-2.29 (m, 1H), 2.21-2.17 (m, 1H), 2.11-2.04(m, 1H), 2.00-1.96 (m, 1H), 1.91-1.85 (m, 2H), 0.85 (s, 3H), 0.77 (s,3H).

Preparative Example 3—Preparation of Thiazole-C^(y) PrecursorsPreparative Example 3.1—1-(5-Bromo-1,3-thiazol-2-yl)cyclobutanol

Step 1:

Isopropylmagnesium chloride/lithium chloride complex (582 mL, 756 mmol)was cooled to 0° C. Thiazole (53.2 mL, 749 mmol) was added over 15minutes, resulting in an orange/red solution. The reaction mixture wasstirred for 20 minutes at 0° C., then allowed to warm to roomtemperature and stirred an additional 2 hours. The reaction mixture wasrecooled to 0° C. and cyclobutanone (53.3 mL, 713 mmol) was added over50 minutes. The mixture was then allowed to warm to room temperature andstirred an additional 20 minutes. The mixture was again cooled to 0° C.and saturated aqueous ammonium chloride was slowly added. The mixturewas diluted with ethyl acetate. The organic layer was separated andwashed with water. The combined aqueous layers were washed with ethylacetate. The combined organic layers were dried over anhydrous magnesiumsulfate, filtered, and concentrated under reduced pressure to afford1-(1,3-thiazol-2-yl)cyclobutanol, which was used without furtherpurification.

Step 2:

1-(1,3-Thiazol-2-yl)cyclobutanol (171.9 g, 1.11 mol) was dissolved inDMF (860 mL) and the mixture was cooled to 0° C. N-Bromosuccinimide (236g, 1.33 mol) was added and the mixture was stirred for 1 hour at 0° C.The solution was poured into cooled water (2 L) containing sodiumsulfite (30 g), and washed with methyl tert-butyl ether (1 L). Themixture was stirred for 10 minutes, then diluted with methyl tert-butylether (1.5 L) and water (500 mL). The organic layer was separated andwashed with water (2 L). The aqueous layer was washed with methyltert-butyl ether (2 L). The combined organic layers were dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure to provide an orange oil. The residue was diluted in hexanes at50° C. (1 L). The mixture was stirred while slowly allowing to cool.Seed crystals were added, and crystallization began around 35° C. Theslurry was stirred overnight at room temperature. The resulting slurrywas cooled to −20° C. and stirred for 20 minutes, filtered, washing withhexane at −20° C. The solid was dried under a nitrogen bag to afford1-(5-bromo-1,3-thiazol-2-yl)cyclobutanol. The filtrate and all remainingmaterial in the flask was diluted in dichloromethane and concentratedunder reduced pressure. To the residue, hexane was added, and thenconcentrated under reduced pressure to 300 mL. The mixture was cooled toroom temperature and seed crystals were added. After crystallizationbegan, the mixture was cooled to −10° C. and filtered, washing withhexane at −10° C. A second crop of crystals allowed to air dry providing1-(5-bromo-1,3-thiazol-2-yl)cyclobutanol. The mother liquor from thesecond filtration was concentrated under reduced pressure. The residuewas purified by column chromatography (ethyl acetate/hexanes) to provide1-(5-bromo-1,3-thiazol-2-yl)cyclobutanol. ¹H NMR (400 MHz, CDCl₃): δ7.58 (s, 1H); 3.56 (br s, 1H); 2.69-2.60 (m, 2H); 2.47-2.36 (m, 2H);2.09-1.87 (m, 2H).

Preparative Example 4—Preparation of Bis-Arylamine Thiazole PrecursorsPreparative Example4.1—1-Methyl-N-(3-methyl-5-(thiazol-5-yl)phenyl)-1H-1,2,4-triazol-3-amine

Step 1:

Dioxane (720 mL) in a 1 L three-necked round bottom flask was degassedfor 30 min. 3-Bromo-5-methylaniline (60 g, 193 mmol),(bispinacolato)diboron (96 g, 377 mmol), potassium acetate (42.7 g, 435mmol), X-Phos (8.3 g, 17.41 mmol) andtris(dibenzylideneacetone)dipalladium(0) (3.99 g, 4.35 mmol) were addedto the degassed solvent under nitrogen. After stirring for 10 minutes atroom temperature, the reaction mixture was heated to an internaltemperature of 80° C. After 4 hours, the heating mantle was removed andreplaced with an ice water bath. The reaction mixture was cooled to 30°C., and was then filtered through a pad of Celite (washing with 500 mLof methyl tert-butyl ether). This was transferred to a 4 L seperatoryfunnel containing pH 8 phosphate buffer (500 mL), brine (500 mL), and anadditional methyl tert-butyl ether (500 mL). The layers were separatedand the organic layer was washed with a 1:1 mixture of brine and water(1 L). The aqueous layers were combined and sequentially back extractedwith a second 500 mL portion of methyl tert-butyl ether. The combinedorganics were treated with 100 g of magnesium sulfate and the resultingmixture stirred for 20 minutes. The resulting suspension was thenfiltered and concentrated under reduced pressure. The resultant residuewas purified by column chromatography on silica gel (0-25% ethyl acetatein hexanes) to yield3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as alight orange solid. MS ESI calc'd. for C₁₃H₂₁BNO₂ [M+H]⁺ 234. found 234.

Step 2:

3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (20.98g, 90 mmol), 5-bromothiazole (8.85 mL, 99 mmol) and sodium carbonate (90mL, 180 mmol) were combined in a flask. 2-Methyl-THF (326 mL) was addedand the mixture was degassed with nitrogen for 1.5 hours before1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (3.67 g, 4.50 mmol) was added. The reaction washeated to 100° C. overnight and was then cooled to room temperature. Thereaction mixture was filtered through a pad of Celite, washing withethyl acetate. The layers were separated and the aqueous layer wasback-extracted with ethyl acetate, dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (0-40% ethyl acetate inhexanes). 3-Methyl-5-(1,3-thiazol-5-yl)aniline was isolated as ayellowish brown solid. MS ESI calc'd. for C₁₀H₁₁N₂S [M+H]⁺191. found191. ¹H NMR (500 MHz, CDCl₃) δ 8.71 (s, 1H), 8.02 (s, 1H), 6.80 (s, 1H),6.71 (s, 1H), 6.50 (s, 1H), 3.71 (s, 2H), 1.79 (s, 3H).

Step 3:

3-Methyl-5-(1,3-thiazol-5-yl)aniline (2 g, 10.51 mmol) was taken up inwater and hexafluorophosphoric acid (23.61 g, 105 mmol) was added underargon. The mixture was cooled to 0° C. and a solution of sodium nitrite(1.09 g, 15.77 mmol) in water (1 mL) was added dropwise. The mixture waswarmed to room temperature and stirred for 30 minutes. The mixture wasdiluted with water until solids crashed out. These solids were collectedby filtration, washed sequentially with water and ether and then driedin vacuo overnight to afford 3-methyl-5-(thiazol-5-yl)benzenediazoniumhexafluorophosphate as a light yellow solid.

Step 4:

3-Methyl-5-(thiazol-5-yl)benzenediazonium hexafluorophosphate (3.22 g,9.27 mmol) was taken up in acetonitrile (93 mL) and copper(II) bromide(4.14 g, 18.55 mmol) was added. The mixture was stirred at roomtemperature for 2 days. The acetonitrile was then removed under reducedpressure, and the residue was taken up in ethyl acetate and 3:1water:ammonium hydroxide. The layers were separated and the aqueouslayer was extracted once more with ethyl acetate. The combined organicswere dried over anhydrous magnesium sulfate, filtered, and absorbed onto10 g of silica. The residue was purified by column chromatography onsilica gel (ethyl acetate/hexanes) to afford5-(3-bromo-5-methylphenyl)-1,3-thiazole. MS ESI calcd. for C₁₀H₉BrNS[M+H]⁺ 254 and 256. found 254 and 256.

Step 5:

A flask was charged with tris(dibenzylidene acetone)dipalladium(0) (144mg, 0.16 mmol), and tert-butyl X-Phos (267 mg, 0.63 mmol). Dioxane (0.5mL) was added, and the mixture was stirred at 100° C. for 10 minutes. Ina separate flask, 1-methyl-1H-1,2,4-triazol-3-amine dihydrochloride (377mg, 2.20 mmol), 5-(3-bromo-5-methylphenyl)-1,3-thiazole (400 mg, 1.57mmol), and cesium carbonate (2.05 g, 6.30 mmol) were combined anddioxane (3.1 mL) was added. The ligand/Pd mixture were sequentiallyadded to this mixture and heated at 100° C. overnight. After cooling toroom temperature, the reaction mixture was diluted with dichloromethaneand loaded directly onto silica. The crude reaction was purified bycolumn chromatography on silica gel (0-10% methanol in dichloromethane)to afford1-methyl-N-(3-methyl-5-(thiazol-5-yl)phenyl)-1H-1,2,4-triazol-3-amine MSESI calc'd. for C₁₃H₁₄N₅S [M+H]⁺ 272. found 272. ¹H NMR (500 MHz,DMSO-d₆) δ 9.19 (s, 1H), 9.03 (s, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.67(s, 1H), 7.32 (s, 1H), 6.95 (s, 1H), 3.77 (s, 3H), 2.27 (s, 3H).

Preparative Example 5—Preparation of Thiazole-C^(y) Arylamine PrecursorsPreparative Example 5.1—5-(3-Bromo-5-methylphenyl)-1,3-thiazole

Potassium carbonate (1.6 g, 11.8 mmol), pivalic acid (0.14 ml, 1.18mmol), 3,5-dibromotoluene (2.94 g, 11.8 mmol), DMA (11 mL) andpalladiumtetrakis (0.27 g, 0.24 mmol) were combined in a flask under anArgon atmosphere and heated to 115° C. overnight. The mixture wasdiluted with water (50 mL), EtOAc (50 mL) and Et₂O (50 mL). The layerswere separated, washed organic with water (2×50 mL), saturated sodiumbicarbonate (25 mL) and brine (25 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography on silica (5-25% EtOAc/hexanes) toafford 5-(3-bromo-5-methylphenyl)-1,3-thiazole as a yellow solid. MS ESIcalcd. for C₁₀H₈BrNS [M+H]⁺ 254. found 254.

Preparative Example5.2—1-[5-(3-Bromo-5-methylphenyl)-1,3-thiazol-2-yl]cyclobutanol

Step 1:

Dioxane (720 mL) in a 1 L three-necked round bottom flask was degassedfor 30 minutes. 3-Bromo-5-methylaniline (60 g, 193 mmol),(bispinacolato)diboron (96 g, 377 mmol), potassium acetate (42.7 g, 435mmol), X-Phos (8.3 g, 17.41 mmol) andtris(dibenzylideneacetone)dipalladium(0) (3.99 g, 4.35 mmol) were addedto the degassed solvent. After stirring for 10 minutes at roomtemperature, the reaction was heated to an internal temperature of 80°C. After 4 hours, the heating mantle was removed and replaced with anice water bath. The reaction mixture was cooled to 30° C., and was thenfiltered through a pad of Celite (washing with 500 mL of methyltert-butyl ether). This was transferred to a 4 L seperatory funnelcontaining pH 8 phosphate buffer (500 mL), brine (500 mL), andadditional methyl tert-butyl ether (500 mL). The layers were cut and theorganic washed with a 1:1 mixture of brine and water (1 L). The aqueouslayers combined and were sequentially back extracted with a secondportion of methyl tert-butyl ether (500 mL). The combined organics weretreated with magnesium sulfate (100 g) and the resulting mixture stirredfor 20 minutes then filtered and concentrated under reduced pressure.The resultant residue was purified by flash chromatography (0-25% ethylacetate in hexanes) to yield3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as alight orange solid. MS ESI calc'd. for C₁₃H₂₁BNO₂ [M+H]⁺ 234. found 234.

Step 2:

2-Methyl THF (720 mL) and aqueous solution of sodium carbonate (2M, 367mL, 734 mmol) were added to a 500 mL three-necked round bottom flask.The solution was degassed for 30 minutes.3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (90 g,367 mmol), 1-(5-bromo-1,3-thiazol-2-yl)cyclobutanol (86 g, 367 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.05 g, 11mmol) were added to the degassed solution. The resulting mixture wasstirred for 5 minutes at room temperature and was then heated to 80° C.After 9 hours, the heating mantle was removed and the reaction wascooled to 30° C. The reaction mixture was filtered through a pad ofSolkaFloc employing water (500 mL) and ethyl acetate (500 mL) tocomplete the transfer. The filtrate was then transferred to a seperatoryfunnel, using an additional 500 mL ethyl acetate and 250 mL brine tocomplete the transfer. The layers were cut, the organic washed with amixture of water and brine (500 mL and 250 mL, respectively), and thenthe aqueous layer was back extracted with ethyl acetate (400 mL). Theorganics were combined, dried over magnesium sulfate (100 g), filtered,and concentrated under reduced pressure to yield a brown crystallinesolid. This material was recrystallized from hot ethyl acetate (250 mLat 60° C.), using hexanes as a counter-solvent (750 mL) to yield1-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]cyclobutanol. MS ESIcalc'd. for C₁₄H₁₇N₂OS [M+H]⁺ 261. found 261. ¹H NMR (600 MHz, DMSO-d₆)δ 7.85 (s, 1H), 6.60-6.51 (m, 2H), 6.42 (s, 1H), 6.30 (d, J=17.6 Hz,1H), 5.11 (s, 2H), 2.53-2.40 (m, 2H), 2.35-2.22 (m, 2H), 2.14 (s, 3H),1.95-1.74 (m, 2H).

Step 3:

1-[5-(3-Amino-5-methylphenyl)-1,3-thiazol-2-yl]cyclobutanol (10.0 g,38.4 mmol) was taken up in water (77 mL) and hexafluorophosphoric acid(79 mL, 576 mmol) was added at room temperature. The mixture was cooledto 0° C., and a solution of sodium nitrite (7.95 g, 115 mmol) dissolvedin water (1 mL) was added dropwise. The mixture was allowed to warm toroom temperature over 30 minutes. The resulting precipitate wascollected via filtration, washed with cold water and ether, and dried invacuo to afford3-(2-(1-hydroxycyclobutyl)thiazol-5-yl)-5-methylbenzenediazoniumhexafluorophosphate as a yellow-brown solid.

Step 4:

3-(2-(1-Hydroxycyclobutyl)thiazol-5-yl)-5-methylbenzenediazoniumhexafluorophosphate (3 g, 7.2 mmol) was taken up in acetonitrile (100mL) and copper(II) bromide (3.21 g, 14.38 mmol) was added. The mixturewas stirred at room temperature overnight. The acetonitrile was thenremoved under reduced pressure and the residue was dissolved inmethylene chloride and washed with brine. The organic layer was driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (ethyl acetate/hexanes) afforded1-[5-(3-bromo-5-methylphenyl)-1,3-thiazol-2-yl]cyclobutanol as an orangeoil. MS ESI calcd. for C14H15BrNOS [M+H]⁺ 324, 326. found 324, 326. 1HNMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 7.35(s, 1H), 6.55 (s, 1H), 2.53-2.48 (m, 2H), 2.47-2.29 (m, 5H), 1.89-1.85(m, 2H).

Preparative Example 5.3—tert-Butylcis-4-[5-(3-bromo-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxycyclohexanecarboxylate

Lithium diisopropylamide (1.8 M in tetrahydrofuran/hexanes/ethylbenzene,2.39 mL, 4.31 mmol) was added dropwise to a cooled −78° C. solution of5-(3-bromo-5-methylphenyl)-1,3-thiazole (730 mg, 2.87 mmol) intetrahydrofuran (12 mL). The mixture was stirred at −78° C. for 35minutes. A solution of tert-butyl 4-oxocyclohexanecarboxylate (854 mg,4.31 mmol) in tetrahydrofuran (4 mL) was added, and the resultingmixture was stirred at −78° C. for 1 hour and then warmed to roomtemperature over 2 hours. The mixture was partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. The layers were separatedand the aqueous layer was extracted once more with ethyl acetate. Thecombined organics were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (ethyl acetate/hexanes) afforded tert-butyl4-[5-(3-bromo-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxycyclohexanecarboxylateas a mixture of diastereomers. The cis and trans diastereomers wereseparated by chiral SFC (Chiral Technology AD-H 2.1×25 cm, 30-75%2-Propanol/CO₂) to afford tert-butylcis-4-[5-(3-bromo-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxycyclohexanecarboxylate.MS ESI calcd. for C₂₁H₂₂BrNO₃ [M+H]⁺ 452, 454. found 452, 454. ¹H NMR(500 MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.64 (s, 1H), 7.43 (s, 1H), 7.36 (s,1H), 5.99 (s, 1H), 2.32 (s, 3H), 2.54-2.21 (m, 1H), 1.91-1.85 (m, 2H),1.80-1.72 (m, 6H), 1.39 (s, 9H).

Prep Exact Mass [M + H]+ Ex. Structure Chemical Name [M + H]+ Observed5.4

methyl 4-(5-(3-bromo-5- methylphenyl)thiazol-2-yl)-4- hydroxy-2,2-dimethylcyclohexanecarboxylate 438/440 438/440

Example 1—Preparation of Compounds of Formula (I) Using the MethodsIllustrated in Scheme 2 Example 1.1—tert-butyl4-hydroxy-4-(5-(3-methyl-5-((1-methyl-1H-1,2,4-triazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexanecarboxylateExample1.2—4-hydroxy-4-(5-(3-methyl-5-((1-methyl-1H-1,2,4-triazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexanecarboxylicacid

Step 1:

In a dry flask, diisopropylamine (0.25 mL, 1.80 mmol) was taken-up inTHF (1.1 mL) under argon and cooled to −78° C. BuLi (1.06 mL, 1.80 mmol)was slowly added, and the resulting mixture was allowed to stir as suchfor 30 minutes.1-Methyl-N-(3-methyl-5-(thiazol-5-yl)phenyl)-1H-1,2,4-triazol-3-amine(150 mg, 0.55 mmol) was taken-up in THF (1.1 mL), and the resultingsolution was added to the LDA mixture. The resulting slurry was stirredas such for 30 minutes, then tert-butyl-4-oxocyclohexanecarboxylate (137mg, 0.69 mmol) was added, and the resulting mixture was allowed to warmto rt overnight. The reaction was quenched with aqueous ammoniumchloride and product was extracted with ethyl acetate (3×). All organicfractions were combined, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography on silica (0-100% ethyl acetate/hexanes) to affordtert-butyl4-hydroxy-4-(5-(3-methyl-5-((1-methyl-1H-1,2,4-triazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexanecarboxylateas a light yellow solid. MS ESI calcd. for C₂₄H₃₁N₅O₃S [M+H]⁺ 470, found470. ¹H NMR δ DMSO-d₆ (ppm) 9.16 (1H, s), 8.18 (1H, s), 7.87 (1H, d,J=1.84 Hz), 7.61 (1H, s), 7.28 (1H, s), 6.89 (1H, s), 5.93 (1H, d,J=2.04 Hz), 3.76 (3H, s), 2.26 (3H, s), 1.60-2.01 (8H, m), 1.39 (9H, s).

Step 2:

In a vial, tert-butyl4-hydroxy-4-(5-(3-methyl-5-((1-methyl-1H-1,2,4-triazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexanecarboxylate(50 mg, 0.10 mmol) was taken-up in acetonitrile (1.1 mL) under argon.Hydrogen chloride in dioxane (0.5 mL, 2.1 mmol) was added, and theresulting mixture was stirred at rt for 2 days. The reaction was dilutedwith DMSO (1 mL), filtered and was purified by reverse phase HPLC(ACN/water with 0.1% TFA modifier) to afford4-hydroxy-4-(5-(3-methyl-5-((1-methyl-1H-1,2,4-triazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexanecarboxylicacid as a light brown solid. MS ESI calcd. for C₂₀H₂₄N₅O₃S [M+H]⁺ 414,found 414. ¹H NMR δ DMSO-d₆ (ppm) 9.16 (1H, s), 8.18 (1H, s), 7.87 (1H,d, J=1.84 Hz), 7.61 (1H, s), 7.28 (1H, s), 6.89 (1H, s), 5.93 (1H, d,J=2.04 Hz), 3.76 (3H, s), 2.26 (3H, s), 1.60-2.01 (8H, m).

Example 2—Preparation of Compounds of Formula (I) Using the MethodsIllustrated in Scheme 1 Example 2.1—tert-butyl4-(5-(3-((1-ethyl-1H-1,2,4-triazol-3-yl)amino)-5-methylphenyl)thiazol-2-yl)-4-hydroxycyclohexanecarboxylateExample2.2—4-(5-(3-((1-ethyl-1H-1,2,4-triazol-3-yl)amino)-5-methylphenyl)thiazol-2-yl)-4-hydroxycyclohexanecarboxylicacid Example2.3—4-(5-(3-((1-Ethyl-1H-1,2,4-triazol-3-yl)amino)-5-methylphenyl)thiazol-2-yl)-4-hydroxycyclohexanecarboxamide

Step 1:

A microwave tube was charged with a stir bar, Pd₂(dba)₃ (20.0 mg, 0.02mmol), tert-butyl X-Phos (37.5 mg, 0.09 mmol),3-amino-1-ethyl-1,2,4-triazole hydrochloride (46.0 mg, 0.31 mmol),tert-butyl4-(5-(3-bromo-5-methylphenyl)thiazol-2-yl)-4-hydroxycyclohexanecarboxylate(100 mg, 0.22 mmol), and cesium carbonate (288 mg, 0.884 mmol). The tubewas fully evacuated and backfilled with argon three times. Degasseddioxane (0.9 mL) was added and the tube was sealed and heated at 100° C.overnight. The reaction mixture was diluted with DCM, loaded directlyonto silica and concentrated under reduced pressure to dryness. Theresidue was purified by column chromatography on silica (0-15%methanol/DCM) to afford tert-butyl4-(5-(3-((1-ethyl-1H-1,2,4-triazol-3-yl)amino)-5-methylphenyl)thiazol-2-yl)-4-hydroxycyclohexanecarboxylateas a brown solid. MS ESI calcd. for C₂₅H₃₃N₅O₃S [M+H]⁺ 484, found 484.

Step 2:

tert-Butyl4-(5-(3-((1-ethyl-1H-1,2,4-triazol-3-yl)amino)-5-methylphenyl)thiazol-2-yl)-4-hydroxycyclohexanecarboxylate(85 mg, 0.18 mmol) was taken-up in methanol (1.2 mL) and THF (2.3 mL).Aqueous potassium hydroxide (370 μl, 2.64 mmol) was added, and theresulting mixture was stirred for 3 days. The reaction was quenched withTFA and directly concentrated under reduced pressure. The crude productwas purified by reverse phase HPLC (ACN/water with 0.1% TFA modifier) toafford4-(5-(3-((1-ethyl-1H-1,2,4-triazol-3-yl)amino)-5-methylphenyl)thiazol-2-yl)-4-hydroxycyclohexanecarboxylicacid as a white solid. MS ESI calcd. for C₂₁H₂₆N₅O₃S [M+H]⁺ 428, found428. ¹H NMR DMSO-d₆ δ (ppm) 9.18 (1H, s), 8.24 (1H, s), 7.88 (1H, s),7.67 (1H, s), 7.25 (1H, s), 6.90 (1H, s), 5.94 (1H, s), 4.09 (2H, q,J=7.24 Hz), 2.26 (3H, s), 1.77-1.91 (9H, m), 1.38-1.45 (3H, m).

Step 3:

In a microwave vial,4-(5-(3-((1-ethyl-1H-1,2,4-triazol-3-yl)amino)-5-methylphenyl)thiazol-2-yl)-4-hydroxycyclohexanecarboxylicacid (15 mg, 0.04 mmol), ammonium chloride (3.75 mg, 0.07 mmol), HATU(26.7 mg, 0.07 mmol), and Hunig's Base (24.5 μL, 0.14 mmol) weretaken-up in DMF (0.7 mL) under argon. The tube was sealed and stirred at65° C. overnight. The reaction mixture was filtered and purified byreverse phase HPLC (ACN/water with 0.1% TFA modifier) to afford4-(5-(3-((1-ethyl-1H-1,2,4-triazol-3-yl)amino)-5-methylphenyl)thiazol-2-yl)-4-hydroxycyclohexanecarboxamideas a white solid. MS ESI calcd. for C₂₁H₂₇N₆O₂S [M+H]⁺ 427, found 427.¹H NMR DMSO-d₆ δ (ppm) 9.18 (1H, s), 8.23 (1H, s), 7.88 (1H, s), 7.67(1H, s), 7.25 (1H, s) 7.22 (1H, s), 6.90 (1H, s), 6.68 (1H, s), 5.91(1H, s), 4.09 (2H, q, J=7.24 Hz), 2.26 (3H, s), 2.12-2.17 (1H, m),1.78-1.85 (6H, m), 1.61 (2H, d, J=11.40 Hz), 1.40 (3H, t, J=7.23 Hz).

The examples in the following tables were prepared in an analogousmanner to that described for Example 2.1, step 1, and where appropriate,step 2 and/or step 3 as well.

Ex. [M + H]+ [M + H]+ No. A′ Chemical Name Calc'd Obsv'd Form(s) 2.4

1-{5-[3-methyl-5-(1H- pyrazol-3-ylamino)phenyl]-1,3-thiazol-2-yl}cyclobutanol 327 327 Free Base 2.5

1-(5-{3-methyl-5-[(5-methyl- 1H-pyrazol-3- yl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutanol 341 341 Free Base 2.6

1-(5-{3-[(5-cyclopropyl-1H- pyrazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2- yl)cyclobutanol 367 367 Free Base 2.7

1-(5-{3-[(5-cyclobutyl-1H- pyrazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2- yl)cyclobutanol 381 381 Free Base 2.8

1-(5-{3-methyl-5-[(3-methyl- 1,2,4-thiadiazol-5- yl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutanol 359 359 Free Base 2.9

1-(5-{3-methyl-5-[(5-methyl- 1H-1,2,4-triazol-3- yl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutanol 342 342 Free Base 2.10

1-(5-{3-methyl-5-[(1-methyl- 1H-1,2,4-triazol-3- yl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutanol 342 342 Free Base 2.11

1-[5-(3-methyl-5-{[1-(1- methylethyl)-1H-1,2,4-triazol-3-yl]amino}phenyl)- 1,3-thiazol-2-yl]cyclobutanol 370 370 FreeBase 2.12

1-(5-{3-[(1-ethyl-1H-1,2,4- triazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2- yl)cyclobutanol 356 356 Free Base 2.13

1-(5-{3-methyl-5-[(1-propyl- 1H-1,2,4-triazol-3- yl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutanol 370 370 Free Base 2.14

1-(5-{3-methyl-5-[(1-phenyl- 1H-1,2,4-triazol-3- yl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutanol 404 404 Free Base 2.15

3-({3-[2-(1- hydroxycyclobutyl)-1,3- thiazol-5-yl]-5-methylphenyl}amino)-N,N- dimethyl-1H-1,2,4-triazole-1- carboxamide 399399 Free Base 2.16

1-(5-{3-[(1-cyclohexyl-1H- 1,2,4-triazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2- yl)cyclobutanol 410 410 Free Base 2.17

1-(5-{3-[(1-cyclobutyl-1H- 1,2,4-triazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2- yl)cyclobutanol 382 382 Free Base 2.18

1-(5-{3-[(1-cyclobutyl-1H- 1,2,4-triazol-5-yl)amino]-5-methylphenyl}-1,3-thiazol-2- yl)cyclobutanol 382 382 Free Base 2.19

1-(5-{3-[(1-benzyl-1H-1,2,4- triazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2- yl)cyclobutanol 418 418 Free Base

Ex. [M + H]+ [M + H]+ No. A′ R^(A*) Chemical Name Calc'd Obsv'd Form(s)2.20

—O—tBu tert-butyl cis-4-hydroxy- 4-[5-(3-methyl-5-{[1-(1-methylethyl)-1H-1,2,4- triazol-3- yl]amino}phenyl)-1,3- thiazol-2-yl]cyclohexanecarboxylate 498 498 Free Base 2.21

—OH cis-4-(5-{3-[(1- cyclobutyl-1H-1,2,4- triazol-5-yl)amino]-5-methylphenyl}-1,3- thiazol-2-yl)-4- hydroxycyclohexane- carboxylic acid454 454 TFA Salt 2.22

—OH cis-4-hydroxy-4-[5-(3- methyl-5-{[1-(1- methylethyl)-1H-1,2,4-triazol-3- yl]amino}phenyl)-1,3- thiazol-2- yl]cyclohexanecarboxylicacid 442 442 Free Base 2.23

—NH₂ cis-4-hydroxy-4-[5-(3- methyl-5-{[1-(1- methylethyl)-1H-1,2,4-triazol-3- yl]amino}phenyl)-1,3- thiazol-2- yl]cyclohexanecarboxamide441 441 Free Base

Ex. [M + H]+ [M + H]+ No. Chemical Name Calc'd Obsv'd Form(s) 2.24(1R,4S or 1S,4R)-4-(5-{3-[(1- 482 482 Freecyclobutyl-1H-1,2,4-triazol-3-yl) Base amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2- dimethylcyclohexanecarboxylic acid 2.25(1R,4S or 1S,4R)-4-(5-{3-[(1- 482 482 Freecyclobutyl-1H-1,2,4-triazol-3-yl) Base amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2- dimethylcyclohexanecarboxylic acid

Example 3—Compounds of Formula (I) Using the General Methods Illustratedin Scheme 4

The description provided in Example 3 is a prophetic example.

Procedure A

This general procedure describes the procedure for conversion of (A1) to(A) as shown in Scheme 4. To a mixture of compound of formula (A1) (1mmol), 1° or 2° alcohol (5 mmol), and triphenylphosphine (resin-bound,1.6 mmol/g loading, 2 mmol) in tetrahydrofuran is added di-tert-butylazodicarboxylate (2 mmol) at 20° C. The reaction mixture is stirred at20° C. for 16 hours. The reaction mixture is diluted with TFA (1 mL) andwater (1 drop). The mixture is stirred for 30 minutes. The mixture isthen filtered through CELITE, washing with dichloromethane (3×). Thefiltrate is concentrated under reduced pressure to afford the cruderesidue TFA salt. The residue is diluted carefully with saturatedaqueous sodium bicarbonate solution and ethyl acetate. The organic layeris separated, washed with brine, dried over magnesium sulfate, filtered,and concentrated under reduced pressure to afford the crude residue freebase. The residue is purified by silica gel chromatography to afford theproduct residue. The residue is lyophilized from acetonitrile and waterto afford a compound of structural subtype (A).

The following compounds could be prepared according to procedures whichare analogous to those described in Example 3, Procedure A.

Ex. No. R^(A) 3.1

3.2

3.3

3.4

3.5

3.6

3.7

3.8

3.9

3.10

3.11

3.12

3.13

3.14

3.15

3.16

3.17

3.18

3.19

3.20

Procedure B

This general procedure describes the procedure for conversion of (A1) to(C) as shown in Scheme 4. A mixture of compound of formula (A1) (1.0mmol), potassium carbonate (2.0 mmol), and sodium iodide (0.50 mmol) inDMF is stirred at 20° C. After 30 minutes, alkyl halide of formula (C1)(0.95 mmol) is added and the reaction mixture is stirred at 20° C. After16 hours, the reaction mixture is diluted with ethyl acetate and washedwith water (4×). The organic layer is separated, washed with brine,dried over magnesium sulfate, filtered, and concentrated under reducedpressure to afford the crude residue. The residue is purified by silicagel chromatography (ethyl acetate/hexanes, linear gradient) to affordthe product residue. The residue is lyophilized from acetonitrile andwater to afford a compound of formula (C).

The following compounds could be prepared according to procedures whichare analogous to those described in Example 3, Procedure B.

Ex. No. R^(A) 3.21

3.22

3.23

3.24

Procedure C

This general procedure describes the procedure for conversion of (A1) to(B) as shown in Scheme 4. To a solution of compound of formula (A1) (1.0mmol) in DMF is added potassium carbonate (2.0 mmol) and sodium iodide(0.20 mmol). After 75 minutes, alkyl halide of formula (B1) (1.0 mmol)is added and the reaction mixture is stirred for an additional 4 hours.The reaction mixture is then partitioned between ethyl acetate andaqueous saturated sodium bicarbonate. The layers are separated, and thenthe organic layer is washed with water (3×) and brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresulting residue is purified by silica gel chromatography (ethylacetate/hexanes, linear gradient) to afford the product residue. Theresidue is lyophilized from acetonitrile and water to afford a compoundof formula (B).

The following compounds could be prepared according to procedures whichwere analogous to those described in Example 3, Procedure C.

Ex. No. R^(A) 3.25

3.26

3.27

3.28

Example 4—Compounds of Formula (I) Using the General Methods Illustratedin Scheme 5

The description provided in Example 4 is a prophetic example.

This general procedure describes the procedure for conversion of (A1) to(D) as shown in Scheme 6. To a suspension of compound of formula (A1)(1.0 mmol) in 1:1 methanol:dichloromethane is addedtrimethylsilyldiazomethane (2.0 M in diethyl ether, 1.0 mmol) at 0° C.The reaction mixture is stirred at 0° C. until all gas evolution ceases.The reaction mixture is allowed to warm to ambient temperature andquenched by the addition of several drops of acetic acid. The reactionmixture is concentrated under reduced pressure and the residue ispurified by silica gel chromatography (ethyl acetate/hexanes, lineargradient) to afford the product residue. The residue is lyophilized fromacetonitrile and water to afford a compound of formula (D).

Example 5—Preparation of Hydroxyalkyl Esters

The description provided in Example 5 is a prophetic example.

A mixture of compounds of formula (A1) (1.0 mmol), potassium carbonate(6.0 mmol) and sodium iodide (1.0 mmol) in DMF is stirred for 10 minutesat ambient temperature. To this mixture is added 2-chloroethanol (4.0mmol) and the reaction mixture is heated at 60° C. for 16 hours. After16 hours, additional 2-chloroethanol (1.0 mmol) is added and thereaction mixture is heated to 65° C. for an additional 2 hours. Thereaction mixture is then diluted with ethyl acetate and washedsequentially with water (3×), aqueous sodium carbonate solution (2×),additional water (3×), and brine (2×). The organic layer is dried overmagnesium sulfate, filtered, and concentrated under reduced pressure toafford the crude product residue. The residue is purified by silica gelchromatography ([3% (1.0 M ammonia in dioxane) in ethyl acetate]/[3%(1.0M ammonia in dioxane) in dichloromethane], linear gradient) toafford a compound of formula (E).

The suitability of the compounds of Formula (I) as prodrugs of Sykinhibitors can be tested as described below.

Hydrolysis Assay:

Analysis of Hydrolysis of Prodrug to Parent Species

The stability of prodrugs is investigated in human liver S9 microsomes.Incubations of prodrugs (10 μM) with liver S9 (1 mg protein/mL) arecarried out at 37° C. in a phosphate buffer, pH 7.4, containing 1 mMNADPH. Control incubations contain BSA (1.1 mg/mL) instead of liver S9microsomes. Aliquots are removed at 0, 5, 15, 30, 60 and 120 min, treatwith 4 volumes of acetonitrile containing 2% formic acid and an internalstandard, and centrifuge. The supernatants are analyzed by LC-MS/MS forprodrug disappearance and appearance of active drug. The half-life ofthe prodrug is calculated from the % prodrug remaining at different timepoints calculated from on the peak area ratio relative to t=0. Theamount of active drug generated at the different time points isdetermined using a standard curve.

Biological Assay

Homogeneous Time-Resolved Fluorescence (HTRF) Assay for the RecombinantHuman Syk Enzyme

A recombinant GST-hSYK fusion protein was used to measure potency ofcompounds to inhibit human Syk activity. The recombinant human GST-SYK(Carna Biosciences #08-176) (5 pM final concentration) was incubatedwith various concentrations of the inhibitor diluted in DMSO (0.1% finalconcentration) for 10 minutes at room temperature in 15 mM Tris-HCl (pH7.5), 0.01% tween 20, 2 mM DTT in 384 well plate format. To initiate thereaction the biotinylated substrate peptide (250 nM final concentration)that contains the phosphorylation site for Syk was added with magnesium(5 mM final concentration) and ATP (25 μM final concentration). Finalvolume of the reaction was 10 μL. Phosphorylation of the peptide wasallowed to proceed for 45′ at room temperature. To quench the reactionand detect the phosphorylated product, 2 nM of aEuropium-anti-phosphotyrosine antibody (Perkin Elmer #AD0161) and 70 nMSA-APC (Perkin-Elmer #CR130-100) were added together in 15 mM Tris pH7.5, 40 mM EDTA, 0.01% tween 20. Final volume of the quenching solutionwas 10 μL.

The resulting HTRF signal was measured after 30 minutes on an EnVision(Perkin-Elmer) reader using a time-resolved fluorescence protocol. TableA below lists activities as IC₅₀ values (nM) for representativecompounds of the invention.

TABLE A Ex. No. rhSyk 1.1 1157 1.2 56.5 2.1 1115 2.2 10.1 2.3 49.6 2.41135 2.5 941.2 2.6 181.2 2.7 273.9 2.8 2689 2.9 1298 2.10 187.7 2.1149.25 2.12 49.1 2.13 96.72 2.14 364.6 2.15 3859 2.16 115.2 2.17 7.4082.18 7706 2.19 324.9 2.20 1002 2.21 3310 2.22 9.941 2.23 36.8 2.240.3876 2.25 2.542

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

What is claimed is:
 1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof, wherein ring A is

R¹ is C₃-C₆ cycloalkyl; R³ is selected from the group consisting of (a)H; (b) C₁-C₃ alkyl; (c) C₁-C₃ alkoxy; and (d) halo; ring C^(y) iscyclobutyl or cyclohexyl; R⁵ is —C(O)OH; R⁶ is C₁-C₃ alkyl or halo; thesubscript r is 1; the subscripts is 0 or 1; and the subscript t is 0, 1,2, 3, 4, or
 5. 2. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof, wherein R³ is H or methyl.
 3. The compound ofclaim 1 or a pharmaceutically acceptable salt thereof, wherein R³ ismethyl.
 4. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein C^(y) is cyclobutyl and the subscripts s and t are both0.
 5. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein C^(y) is cyclohexyl; R⁵ is —C(O)OH; R⁶ is methyl; thesubscripts is 1; and the subscript t is 0, 1, or
 2. 6. The compound ofclaim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is selected from the group consisting of:1-(5-{3-[(1-cyclohexyl-1H-1,2,4-triazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol;1-(5-{3-[(1-cyclobutyl-1H-1,2,4-triazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol;1-(5-{3-[(1-cyclobutyl-1H-1,2,4-triazol-5-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol;cis-4-(5-{3-[(1-cyclobutyl-1H-1,2,4-triazol-5-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxycyclohexanecarboxylicacid;(1R,4S)-4-(5-{3-[(1-cyclobutyl-1H-1,2,4-triazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylicacid; and(1S,4R)-4-(5-{3-[(1-cyclobutyl-1H-1,2,4-triazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylicacid.
 7. A pharmaceutical composition comprising the compound of claim 1or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 8. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein the compound iscis-4-(5-{3-[(1-cyclobutyl-1H-1,2,4-triazol-3-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylicacid.